Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21]C(OC(C)(C)C)=O)[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH2:21])[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(N)Cc2c[nH]cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq.), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1 M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%-6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCI (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%-6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10-3.30 (m, 2), 3.20-3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55-7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Product: NC(=O)c1ccc(N2CCNCC2)nc1
Yield: 6.2 %

Procedure:
Using 6-chloronicotinamide (5.00 g) and piperazine (27.6 g), and by reaction in the same manner as in Example 196 (1) at 100° C., 1-(5-carbamoyl-2-pyridyl)piperazine (0.41 g) was obtained as a yellow powder.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([S:19][C:20]1[S:21][C:22]([C:26]#[N:27])=[C:23](Cl)[N:24]=1)[CH2:16][CH2:17][CH3:18]>C(#N)C>[CH2:15]([S:19][C:20]1[S:21][C:22]([C:26]#[N:27])=[C:23]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:24]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCSc1nc(Cl)c(C#N)s1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCSc1nc(Sc2ccccc2)c(C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.15 ml (5.55 g) of thiophenol and 7.0 ml of triethylamine are added successively while stirring to a solution of 10.93 g of 2-n-butylthio-4-chloro-5-cyanothiazole prepared according to Example V(b), in 100 ml of acetonitrile. After stirring at room temperature for another hour and leaving to stand overnight, the reaction mixture is evaporated. The residue is dissolved in methylene chloride, after which the organic solution is successively washed with water, 1N sodium hydroxide solution and water, and is then dried, filtered and evaporated. Chromatography in petroleum ether (40-60)/diethyl ether 3:1 v/v as a solvent over a 1400 ml dry silica gel column provides the desired product in a yield of 7.24 g; oil; Rf (petr.ether/diethyl ether 3:1 v/v) 0.35; identification by means of I.R. spectrum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH3:2].[H][H]>C1COCC1.[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1N1CCCCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1cc(N)ccc1N1CCCCC1=O

Procedure:
235 mg (0.889 mmol) of the product from example 90A are dissolved in 40 ml of THF and admixed with 50 mg of 10% palladium on activated carbon. Hydrogenation is effected in a hydrogen atmosphere under standard pressure overnight, then the mixture is filtered with suction through kieselguhr, washed three times with THF and concentrated cautiously under reduced pressure. This affords 262 mg of crude product, which is converted further without purification.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[P:30]([O:42][CH2:43][C@H:44]1[O:48][C@@H:47]([N:49]2[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]2=[O:51])[C@H:46]([OH:57])[C@@H:45]1[OH:58])([O:33][P:34]([O:37][P:38]([OH:41])([OH:40])=[O:39])([OH:36])=[O:35])(=[O:32])[OH:31].C([NH+](CCCC)CCCC)CCC>CN(C=O)C.C(N(CCCC)CCCC)CCC>[OH:40][P:38]([O:37][P:34]([O:33][P:30]([O:42][P:30]([OH:33])([OH:32])=[O:31])([OH:31])=[O:32])([OH:36])=[O:35])(=[O:39])[OH:41].[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C@@H:47]1([N:49]2[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:44]([CH2:43][OH:42])[C@@H:45]([OH:58])[C@H:46]1[OH:57]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Temperature: 50 °C
Reaction time: 72 h

Procedure:
Uridine 5′-monrophosphate (Sigma, Milwaukee, 3.0 g, 9.26 mmol) was dissolved in dry DMF (10 mL) and tributylamine (Aldrich, 2 mL). The solution was evaporated in vacuo at 40° C. to an oil. The residue was dissolved in dry DMF (Aldrich, 8 mL) to form a solution. Carbonyldiimidazole (Aldrich, 1.65 g, 10.18 mmol) was added to this solution. The reaction was heated at 50° C. for one hour. Uridine 5′-triphosphate (Yamasa, 5.60 g, 10.18 mmol) prepared as the anhydrous tributylammonium salt in DMF (5 mL) and tributylamine (2 mL), as described in Example 3 below, was added to the reaction solution. The mixture was allowed to stir at 50° C. for three days when the solution was evaporated in vacuo to an oil, redissolved in water (5 mL) and purified by column (300×50 mm) chromatography (Sephadex DEAE-A25, 40-120μ, Aldrich, pre-swollen in 1.0 M NaHCO3 and washed with 2 column volumes of deionized H2O) (H2O→0.3 M NH4HCO3 gradient). The pure fractions were concentrated in vacuo at 35° C., and H2O added and reevaporated 5 times to obtain diuridine tetraphosphate tetrammonium salt as a white solid (2.37 g, 30% yield): 92.11% pure by HPLC with the same retention time as the standard. In addition, the tetrammonium salt was analyzed by FABMS to give a mass of [C18H25N4O23P4 (M—H+)−: calculated 788.9860] 788.9857, confirming a parent formula of C18H26N4O23P4 for the free acid].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([C:16]1[S:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CO.Cl[Pd]Cl.O>[C:12]([C:16]1[S:20][C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(C(C)(C)C)s2)c1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
Methyl 2-chloroisonicotinate (175 mg, 1.02 mmol), 2-(5-tert-butylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.13 mmol), K2CO3 (85 mg, 0.61 mmol) and PdCl2 (dppf) (37.3 mg, 0.05 mmol) was stirred in methanol (2 mL) and heated in a single node microwave reactor to 100° C. for 30 min. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (50 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 50 g column. A gradient from 5% EtOAc in heptane over 2 CV followed by 5% to 20% of EtOAc in heptane over 9 CV was used as mobile phase. The product was collected using the wavelength 295 nm. The product fractions were collected and evaporated in vacuo yielding methyl 2-(5-tert-butylthiophen-2-yl)isonicotinate (213 mg, 76%). 1H NMR (600 MHz, cdcl3) δ 1.41 (s, 9H), 3.96 (s, 3H), 6.85 (d, 1H), 7.50 (s, 1H), 7.61 (d, 1H), 8.13 (s, 1H), 8.64 (d, 1H). MS m/z 276 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([N:10]1[C:15](=[O:16])[C:14]2[N:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]([CH2:21][C:22]2[C:26]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=3[S:24][N:23]=2)[C:11]1=[O:33])[CH2:8][CH3:9])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:32][C:27]1[C:26]2[C:22]([CH2:21][N:12]3[C:13]4[CH:20]=[CH:19][CH:18]=[N:17][C:14]=4[C:15](=[O:16])[N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([OH:34])=[O:5])[C:11]3=[O:33])=[N:23][S:24][C:25]=2[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](C(=O)O)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Yield: 88.5 %

Procedure:
A solution of 32 mg of (S)-2-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-butyric acid tert-butyl ester in 20% trifluoroacetic acid in dichloromethane (1 mL) is stirred at room temperature for 45 min. The resulting mixture is concentrated to give 25 mg (89%) of (S)-2-[1-(4,6-Dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-butyric acid; LCMS (ESMS): m/z 426 (M+H+).
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[Cl:22])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:22][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:21])[C:13]=1[N:12]1[CH:11]=[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]2=[N:1]1)[C:17]#[N:18]
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)c(-n2cc3cncc(Cl)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A suspension of 4-{[1-(4-azido-5-chloropyridin-3-yl)meth-(E)-ylidene]amino}-3,5-dichlorobenzonitrile (3.8 g, 10.95 mmol) in toluene (45 mL) was heated to reflux for 18 hours and then cooled to room temperature. The precipitated solid was removed by filtration and washed sequentially with toluene, ethyl acetate and DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane) and then triturated with diethyl ether to afford the title compound as an off-white solid (2.5 g, 71% yield). 1H NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 7.86 (s, 2H).
Reaction SMILES: [I:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[NH2:8].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][N:4]=[C:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]=1[I:1])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cnc(-c2ccccc2)c(I)c1N
Solvent: CC(C)=O
Product: COc1cnc(-c2ccccc2)c(I)c1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of 159 g (4.88 mmol) 3-iodo-5-methoxy-2-phenyl-pyridin-4-ylamine in 30 ml acetone was added dropwise 0.98 ml (7.31 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 5 h before being cooled to room temperature concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 1.61 g (67%) 1-benzoyl-3-(3-iodo-5-methoxy-2-phenyl-pyridin-4-yl)-thiourea as a yellow crystalline solid. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: C([O:4][C:5]([C:7]1[C:8]([O:15][CH2:16][CH:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1)=[O:6])C=C.N1CCOCC1>C1COCC1.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>[C:13]([C:10]1[N:9]=[C:8]([O:15][CH2:16][CH:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[CH2:19][CH2:18]2)[C:7]([C:5]([OH:6])=[O:4])=[CH:12][N:11]=1)#[N:14]
Reactant: C=CCOC(=O)c1cnc(C#N)nc1OCC1CCC2(CC1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: N#Cc1ncc(C(=O)O)c(OCC2CCC3(CC2)CC3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a 2-cyano-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester (0.096 mmol) in THF (1.0 mL) are added Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) (0.0096 mmol) and morpholine (0.19 mmol) at room temperature. The reaction mixture is stirred at room temperature for 0.5 h and the reaction is quenched by the addition of sat. aq. NaHCO3. The mixture is extracted with ether. The aqueous layer is acidified to pH 2 with sat. aq. KHSO4. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude titled compound.
Reaction SMILES: [Br:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:38]([F:42])([F:41])([F:40])[F:39]>C(OCC)C>[F:39][B-:38]([F:42])([F:41])[F:40].[Br:1][CH2:2][S+:3]([C:18]1[CH:17]=[C:16]([CH3:19])[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)CBr)cc1
Reactant: Cc1ccc(C)c(C)c1C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CBr)c2cc(C)c(C)c(C)c2C)cc1
Reaction time: 0.5 h

Procedure:
1-((Bromomethyl)sulfinyl)-4-methylbenzene (200 mg, 0.86 mmol) of example 35 was dissolved in dry diethyl ether (6 mL) under an argon atmosphere. 1,2,3,4-tetramethylbenzene (0.127 g, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.145 mL, 1 eq) was slowly added maintaining the same temperature. After 30 minutes, HBF4 in diethyl ether was added (54%, 0.209 mL, 1.5 eq). The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and dried under vacuum. 0.309 g (82%) of the desired product was obtained as a white solid. mp: 238° C. 1H NMR (DMSO-d6, 400 MHz): δ 7.98 (2H, d, J=8.4 Hz), 7.78 (1H, s), 7.58 (2H, d, J=8.2 Hz), 6.8 (2H, ABQ, J=9.08 Hz), 2.51 (3H, s), 2.42 (3H, s), 2.36 (3H, s), 2.26 (3H, s), 2.25 (3H, s). 13C NMR (DMSO-d6, 100 MHz): δ 145.7, 142.8, 138.4, 137.3, 136.8, 131.6, 130.6, 126.2, 121.4, 120.5, 35.0, 20.9, 20.4, 17.1, 16.4. FT-IR (KBr): 3048, 2967, 1494, 1446, 1392, 1284, 1261, 1218, 1195, 1085, 1051, 1031, 862 cm−1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[OH-].[NH4+].C(OCC)(=O)C>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3
Reactant: Cc1c[nH]c(-c2cc(SCCNC(=O)OC(C)(C)C)c3c(F)ccc4c3c2C(=O)N4)c1C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1c[nH]c(-c2cc(SCCN)c3c(F)ccc4c3c2C(=O)N4)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [2-[6-fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester (from Example 49 above) (66 mg, 0.145 mmol) in CH2Cl2 (5 mL) was added TFA (Aldrich, 2.5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Aqueous ammonium hydroxide (4 mL) and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by RP-HPLC (C-18, eluted with 1% acetonitrile/0.05% TFA in H2O) to give 5-(2-amino-ethylsulfanyl)-6-fluoro-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt as a yellow-green solid. (Yield 20 mg, 29.4%).
Reaction SMILES: I[C:2]1[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.[OH-].[Na+]>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.COCCOC>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: COc1ccccc1B(O)O
Reactant: CN(C)[c-]1cccc1I
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc[c-]1N(C)C
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Racemic iodide 12i (101 mg, 0.28 mmol), 2-methoxyphenylboronic acid (86 mg, 0.57 mmol) and Pd(PPh3)4 (33 mg, 2.86×10−2 mmol) were added to a dry Schlenk flask, followed by DME (3 mL) and an aqueous solution of 3 M aqueous NaOH (0.24 mL, 0.70 mmol). Argon was bubbled through the resulting mixture for 10 minutes, and the system was heated to reflux for 14 h. The reaction mixture was allowed to cool to room temperature, diluted with Et2O, washed with water (1×5 mL), brine (1×5 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. Gradient flash column chromatography (silica gel, 98:2→95:5 hexane/EtOAc) afforded 57 (83 mg, 87%) as an orange oil that solidified on standing: Rf 0.19 (95:5 hexane/EtOAc); mp 92-93° C. (hexane); IR (KBr) vmax 3082, 2941, 2833, 2776, 1597, 1450, 1411 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, 1H, J=7.5, 1.8 Hz), 7.26 (td, 1H, J=7.8, 1.8 Hz), 7.02 (td, 1H, J=7.5, 0.9 Hz), 6.87 (d, 1H, J=8.4 Hz), 4.27 (t, 1H, J=3.6 Hz), 4.24 (s, 5H), 4.09 (t, 1H, J=2.1 Hz), 4.05 (t, 1H, J=2.7 Hz), 3.79 (s, 3H), 2.47 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.5, 132.6, 127.5, 127.0, 120.0, 113.1, 110.5, 75.5, 68.9, 66.8, 62.0, 56.8, 55.6, 44.1; EIMS [m/z (%)] 335 (M+, 100), 229 (24); HRMS (EI) calcd for C19H21NO88Fe: 335.0972. Found 335.0978.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.[CH2:28]=O.C[O-].[Na+].[BH4-].[Na+].[OH-].[Na+]>CO.O>[OH:1][C@H:2]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH3:28])=[CH:14][CH:15]=1
Reactant: CN1C(=O)C[C@H](c2ccc(N)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1ccc([C@H]2CC(=O)N(C)[C@H]2[C@H](O)c2ccc(-c3ccccc3)s2)cc1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A mixture of (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-aminophenyl)-1-methylpyrrolidin-2-one (Example 17, 105 mg, 0.30 mmol), paraformaldehyde (13 mg, 0.42 mmol) and sodium methoxide (81 mg, 1.5 mmol) in methanol (1 mL) was stirred overnight. After adding sodium borohydride (12 mg, 0.30 mmol) the reaction mixture was heated at the reflux temperature for 1 h, then treated with a 1M NaOH solution (1 mL). The resulting mixture was stirred for 10 min, diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The organic layer was washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure to give a yellow solid. The crude product was sequentially triturated with EtOAc, Et2O and hexane to provide (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]methyl-4-[4-(methylamino)phenyl]pyrrolidin-2-one (89 mg, 76%) as a white solid: TLC (EtOAc) Rf 0.34; mp: 212° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:28]=5)[C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH3:35][N:36]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[C:21]([C:24]6[CH:25]=[N:26][N:27]([CH:29]7[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]7)[CH:28]=6)[C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:38]=[N:37]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(-c3cnn(C)c3)nn12
Temperature: 100 °C

Procedure:
A suspension of 7-[(S)-1-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)furo[3,2-c]pyridin-6-ylamine (0.289 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.507 mmol, 2.7 eq), Pd(PPh3)4 (66.8 mg, 0.0578 mmol, 20 mol %), and K2CO3 (200 mg, 1.45 mmol, 5.0 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated in a microwave reactor at 100° C. for 0.5 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by chromatography on an SCX column and HPLC giving the title compound as a diformate salt. 1H NMR (400 MHz, CD3OD): δ=2.15 (d, J=6.8 Hz, 3H), 2.25-2.40 (m, 4H), 3.18-3.28 (ddd, J=12.9, 11.6, 3.8 Hz, 2H), 3.59 (dt, J=13.3, 3.3 Hz, 2H), 3.85 (s, 3H), 4.60 (dddd, J=10.0, 4.9, 4.8 Hz, 1H), 6.34 (q, J=6.6 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 7.84 (s, 2H), 8.03 (s, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.34 (br s, 4H). MS (ES+): m/z 526.17 (20) [MH+]. HPLC: tR=1.94 min (ZQ3, polar—5 min).