Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C1(C)C=CC=CC=1>[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[CH:12]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1CCc2ccccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCc3ccccc3C2)c2ccccc2C1
Yield: 96.9 %

Procedure:
Tetrahydroisoquinoline (Aldrich Chemical, 18.0 g, 135.1 mmol), 1-indanone (10.0 g, 75.1 mmol) and P2O5 (2.30 g, 16.1 mmol) in 150 mL of toluene were stirred under nitrogen and refluxed for 10 h with water removal via a Dean Stark apparatus. Upon cooling a large amount of fine white powder precipitated (as amine phosphate salts). The dark green solution was filtered under N2 through a medium porosity frit and assayed by NMR after tolune removal (about 85:15 mole ratio of product to ketone). Solvent was evaporated and indanone/amine (about 3.0 g) was removed in vacuo (90-160° C. at 0.5 mm Hg, 76 Pa). The process was stopped and the crude enamine residue recovered under inert atmosphere, giving 18.0 g of dark red-green oil, 95 percent yield. The crude product was analyzed by 1H and 13C NMR and showed less than 2 percent mole ketone.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:19]=3[CH:18]=2)[C:14]([CH3:29])=[CH:13][N:12]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([NH2:47])[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH:38]([NH:47][C:26]([C:25]2[C:19]3[CH:18]=[C:17]([C:15]4[C:14]([CH3:29])=[CH:13][N:12]=[C:11]([Cl:10])[N:16]=4)[S:21][C:20]=3[CH:22]=[CH:23][CH:24]=2)=[O:28])[C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:44][CH:43]=1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)O)cccc2s1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4C)cc23)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Diisopropylethylamine (1.80 mL, 10.3 mmol) is added to a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (3.00 g, 9.84 mmol) in anhydrous dichloromethane (100 mL) at 0° C. under nitrogen to form a solution, then followed by the successive addition of C,C-bis-(4-methoxyphenyl)-methylamine (2.51 g, 10.3 mmol) and powdered 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.56 g, 10.3 mmol). The resultant mixture is allowed to stir at 0° C. for 1 hour, then at room temperature for 3 hours. Diethyl ether (50 mL) is added in small portions to the mixture, the mixture is stirred for another 10 minutes before filtration. After vacuum drying at 35° C., the crude title compound (5.19 g) is obtained as a tan solid. It is used without further purification.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[CH:19]12[O:27][CH:23]([CH2:24][NH:25][CH2:26]1)[CH2:22][N:21]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1)[CH2:20]2>CN(C=O)C>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:21]2[CH2:22][CH:23]3[O:27][CH:19]([CH2:26][N:25]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:24]3)[CH2:20]2)=[CH:39][CH:38]=1)#[N:37]
Reactant: N#Cc1ccc(CCCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 54 °C
Reaction time: 24 h

Procedure:
Triethylamine (2.2 mL, 0.016 mol) and tert-butyl 2-bromoethylcarbamate (see Preparation R above, 2.83 g, 0.013 mol) were added to a solution of 4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (see Preparation G above, 3.0 g, 0.011 mol) in DMF (50 mL). The mixture was stirred for 24 h at 54° C., cooled to 25° C., and concentrated in vacuo. The residue was dissolved in chloroform and washed with saturated sodium chloride. The aqueous layer was separated and extracted with chloroform (2×150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was chromatographed on silica gel, eluting first with chloroform:acetonitrile:conc. ammonium hydroxide (9:1:0.02) until the higher Rf impurities were removed. Then the eluent was switched to chloroform:methanol:conc. ammonium hydroxide (9:1:0.02). This afforded 2.76 g (61%) of the title compound.
Reaction SMILES: I[CH3:2].[I-].[Na+].C[O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1>CC#N>[CH3:2][N:12]1[CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:6]
Reactant: CI
Reactant: COc1ccc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)ccc1=O
Temperature: 45 °C

Procedure:
Iodomethane (0.063 mL, 1.007 mmol) and sodium iodide (151 mg, 1.007 mmol) were added to a solution of N-[3-(6-methoxypyridin-3-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (109 mg, 0.315 mmol) in MeCN (3.1 mL) at room temperature under nitrogen. The mixture was heated to 45° C. for 72 hours, then cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 1-methyl-5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2(1H)-one as an off-white solid. MS APC calc'd for C17H14F3N4O [M+H]+ 347. found 347. Check LCMS data. 1H NMR (400 MHz, Acetone-d6): δ 9.31 (s, 1H); 8.83 (d, J=4.9 Hz, 1H); 8.72 (s, 1H); 7.96 (d, J=8.2 Hz, 1H); 7.84 (d, J=7.8 Hz, 1H); 7.79 (t, J=7.8 Hz, 1H); 7.54 (d, J=7.4 Hz, 1H); 7.48 (t, J=7.9 Hz, 1H); 7.24 (d, J=4.9 Hz, 1H); 6.76 (d, J=8.2 Hz, 1H); 4.04 (s, 3H). APCI: [M+H]+ m/z 347.1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:36](=[O:37])[C@H:32]([CH:33]([CH3:34])[CH3:35])[NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (1.0 g, 4.2 mmol) in CH2Cl2 (21 mL) was treated with Et3N (0.76 mL, 5.44 mmol), dl-N-(tert-butoxycarbonyl)valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (20 mL), and washed with 2 N NaOH solution (2×20 mL), brine (1×20 mL) and dried (MgSO4). Concentration and chromatography (SiO2, 3% CH3OH/CH2Cl2) afforded 1-(4-chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 60%) as a pale amber oil: ESI/MS m/e 438 (M++H)
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5](COCC[Si](C)(C)C)[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]4[N:27]=[CH:28][CH:29]=[C:30]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[C:25]4=[N:24][C:23]=3[CH2:37][CH2:38][C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)=[CH:18][CH:17]=2)=[N:3]1.CCOCC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]4[N:27]=[CH:28][CH:29]=[C:30]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[C:25]4=[N:24][C:23]=3[CH2:37][CH2:38][C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)=[CH:20][CH:21]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)n(COCC[Si](C)(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nc(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of compound 51e (0.20 g, 0.29 mmol) in TFA/DCM (1:3 v/v, 5 mL) was stirred overnight at rt. The mixture was concentrated under reduced pressure, and the residue obtained was treated with Et2O (10 mL). The solids formed were collected by filtration, washed with Et2O (2×20 mL), and treated with MeOH (5 mL) and DIEA (0.5 mL). The resulting solution was stirred at 70° C. for 30 min and allowed to cool to rt. The solids formed were collected by filtration and washed with Et2O (2×20 mL) to obtain the title compound 78 as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 12.30 (s, 1H), 8.21 (d, J=8.7 Hz, 1H), 8.08 (d, J=5.4 Hz, 1H), 7.85-7.92 (m, 4H), 7.76-7.67 (m, 3H), 7.55-7.50 (m, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.34 (d, J=5.7 Hz, 1H), 3.92-3.85 (m, 4H), 3.78-3.70 (m, 4H), 3.39-3.34 (m, 7H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H28N8O2: 533.2 (M+H). Found: 533.3.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1/[CH2:4][CH:5]2[N:16]([CH2:17]/1)[C:14](=[O:15])[C:13]1[C:8](=[CH:9][C:10]([OH:20])=[C:11]([O:18][CH3:19])[CH:12]=1)[N:7]=[CH:6]2.[C:21](=[O:24])([O-])[O-].[K+].[K+].C(OC([NH:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[C:42]([CH2:44]Br)[CH:41]=[C:40]([CH2:46]Br)[CH:39]=1)=O)C=C.[I-].[K+]>CN(C)C=O>[NH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([CH2:46][O:20][C:10]2[C:11]([O:24][CH3:21])=[CH:12][C:13]3[C:14](=[O:15])[N:16]4[CH2:17][C:3](=[CH:2][CH3:1])[CH2:4][C@H:5]4[CH:6]=[N:7][C:8]=3[CH:9]=2)[CH:41]=[C:42]([CH2:44][O:20][C:10]2[C:11]([O:18][CH3:19])=[CH:12][C:13]3[C:14](=[O:15])[N:16]4[CH2:17][C:3](=[CH:2][CH3:1])[CH2:4][C@H:5]4[CH:6]=[N:7][C:8]=3[CH:9]=2)[CH:43]=1
Reactant: C=CCOC(=O)NCCCOc1cc(CBr)cc(CBr)c1
Reactant: C/C=C1/CC2C=Nc3cc(O)c(OC)cc3C(=O)N2C1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=C1C[C@H]2C=Nc3cc(OCc4cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)cc(OCCCN)c4)c(OC)cc3C(=O)N2C1
Temperature: 30 °C
Reaction time: 20 h
Yield: 0.7 %

Procedure:
To a stirred solution of pre-tomaymycin (21 mg) in dimethylformamide (0.7 mL), were added potassium carbonate (32 mg), 1-(3-allyloxycarbonylamino-propyloxy)-3,5-bis-(bromomethyl)-benzene (16.2 mg) and potassium iodide (12.8 mg). The reaction was stirred for 20 h at 30° C. Solids were filtered off, washed twice with dimethylformamide (0.2 mL) then discarded. Water (0.5 mL) was added to the combined dimethylformamide solution and the resulting precipitate was filtered off, washed with water and dried by centrifugal evaporation over a Jouan Model RC10.10 apparatus. To the crude compound (27 mg) dissolved in dimethylformamide (0.8 mL), tetrakis(triphenylphosphine) palladium (2 mg), triphenylphosphine (0.9 mg) and pyrrolidine (5.6 μL) were added. After stirring for 15 h at 30° C., tetrakis(triphenylphosphine) palladium (2 mg), triphenylphosphine (1 mg) and pyrrolidine (2.8 μL) were added and the reaction mixture was stirred at room temperature for another 15 h. Water (0.4 mL) was added to the dimethylformamide solution and formic acid was added until complete dissolution of the precipitate. The resulting solution was injected for HPLC purification according to method B1. The appropriate fractions were combined and concentrated by centrifugal evaporation over a Jouan Model RC10.10. apparatus to afford 8,8′-[5-(3-aminopropyloxy)-1,3-benzenediylbis-(methylenoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] (0.2 mg).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[O:10][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].BrC(C)C.O>CS(C)=O>[CH3:13][C:11]1[O:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([O:7][CH:2]([CH3:3])[CH3:1])[CH:12]=1
Reactant: CCOC(=O)c1oc(C)cc1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Solvent: O
Product: CCOC(=O)c1oc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 1.6 g (14.3 mmol, 1.2 equiv) of potassium tert-butoxide in 11 mL of dimethyl sulfoxide is added to a solution of 2.0 g (11.8 mmol) of ethyl 3-hydroxy-5-methyl-2-furancarboxylate (Takei, H. and Mukaiyama, T., Bull. Soc. Chem. Jpn., 43, 3607 (1970)) in 40 mL of dimethyl sulfoxide under a nitrogen atmosphere. The resulting solution is stirred at room temperature for 1 hour and treated with 5.9 g (47.9 mmol, 4.1 equiv) of 2-bromopropane. The reaction is stirred at room temperature for 7.5 hours under nitrogen and poured onto 100 mL of water. The aqueous solution is extracted with ethyl acetate (4x). The combined extracts are washed with water (2x) and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give 1.7 g (2.5 g theo., 68%) of ethyl 5-methyl-3-isopropoxy-2-furancarboxylate as a pale, yellow oil.
Reaction SMILES: C[O-].[Na+].Cl[CH:5](Cl)[C:6]([O:8][CH3:9])=[O:7].[CH:11](=O)[CH3:12].[NH2:14][C:15]([NH2:17])=[S:16]>C(OCC)C.O>[NH2:17][C:15]1[S:16][C:11]([CH3:12])=[C:5]([C:6]([O:8][CH3:9])=[O:7])[N:14]=1
Reactant: CC=O
Reactant: COC(=O)C(Cl)Cl
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1nc(N)sc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
Sodium methoxide (25% wt solution, 50 mL) was added slowly to a 0° C. solution of methyl 2,2-dichloroacetate (25 mL, 261 mmol) and acetaldehyde (15 mL, 267 mmol) in 200 mL diethyl ether. The mixture was stirred at 0° C. for 1 hour. Water (100 mL) was added, and the organic layer was recovered. The aqueous phase was extracted with diethyl ether (2×100 mL). The organic extracts were combined, washed with brine (2×200 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude oil (29 g) was dissolved in MeOH (250 mL), and thiourea (15.5 g, 190 mmol) was added. The solution was stirred at reflux for 4 hours. After cooling to room temperature, the solvent was evaporated. The oily residue was dissolved in MeOH (50 mL). The solution was poured into ice/water (500 mL). The pH was brought to approximately 8-9 with concentrated ammonium hydroxide. The yellow solid material was recovered by filtration, washed with water (3×50 mL) and hexanes (3×50 mL), and dried in vacuo, affording methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (11.7 g, 26%) as a yellow solid. The product was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:17])[C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
7.3 g 7-Nitro-4H-benzo[1,4]thiazin-3-one was suspended in 65 ml DMF and treated in portions with 1.6 g of 55% sodium hydride. Stirring a room temperature was continued for 0.5 hrs, than 5.2 g methyl iodide in 15 ml DMF were added dropwise. After another 3 hrs the mixture was poured into ice water and the title product isolated by filtration in a yield of 7.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:39][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:40][C:41]([CH3:43])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:39][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][N:36]([CH:41]([CH3:43])[CH3:40])[CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(C)=O
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(C4CCNCC4)cc3-5)cc2Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(n2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
To a solution of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-piperidin-4-yl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (40 mg, 0.07 mmol, 1 eq) in THF (1 mL) was added acetone (8 mg, 0.14 mmol, 2 eq), sodium triacetoxyborohydride (23 mg, 0.11 mmol, 1.5 eq) and trace amount of acetic acid. It was stirred at rt for 16 h. The mixture was purified by preparative HPLC to yield the desired product (15.4 mg, 36%). 1H-NMR (DMSO-d6) δ 8.41 (broad, 1H), 8.32 (d, 1H), 8.01 (d, 1H), 7.74 (d, 1H), 7.5 (dd, 1H), 7.44 (m, 1H), 7.29 (m, 2H), 7.20 (d, 1H), 7.15 (m, 1H), 5.24 (s, 2H), 4.04 (m, 1H), 3.36 (m, 4H), 2.92 (m, 3H), 2.74 (m, 1H), 2.25 (m, 1H), 2.02 (m, 2H), 1.89 (m, 2H), 0.99 (d, 6H). LCMS RT=2.87 min; [M+H]+=603.2.
Reaction SMILES: [C:1]1(=[O:26])[C:5]2[C:6]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[NH:18][C:7]=3[CH2:8][C:9]3[NH:10][C:11]4[C:16]([C:17]=3[C:4]=2[C:3](=[O:25])[NH:2]1)=[CH:15][CH:14]=[CH:13][CH:12]=4>Cl.O.CCO.C1(C)C=CC=CC=1.[Zn].Cl[Hg]Cl>[C:3]1(=[O:25])[CH:4]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][C:9]=3[CH2:8][C:7]3[NH:18][C:19]4[C:24]([C:6]=3[CH:5]2[C:1](=[O:26])[NH:2]1)=[CH:23][CH:22]=[CH:21][CH:20]=4
Reactant: O=C1NC(=O)C2=C1c1c([nH]c3ccccc13)Cc1[nH]c3ccccc3c12
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)C2c3c([nH]c4ccccc34)Cc3[nH]c4ccccc4c3C12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.20 g (18.4 mmol) of Zn granules are washed with 2×3 ml of 2 N HCl, then immediately added to 90 mg (0.33 mmol) of HgCl2 in 1.5 ml of H2O and 1.5 ml of conc. HCl and the mixture is shaken at room temp. for 10 min. The aq. phase is decanted and the zinc amalgam is additionally washed with 2×3 ml of dil. HCl before it is added to a solution of 60.0 mg (0.18 mmol) of 1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]cyclohepta[b]indole-1,3-dione in 1.5 ml of 5 N HCl, 1.5 ml of EtOH and 1.5 ml of toluene and heated under reflux. After 1 h, as soon as the reaction solution has cooled to room temp. H2O is added and the mixture is extracted with 2×10 ml of CH2Cl2. The org. extracts are dried over Na2SO4, concentrated in vacuo and purified by column chromatography (SiO2; CH2Cl2/ethyl acetate/MeOH 8:2:0.5): colorless wax, yield 14 mg (23%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](Br)[CH2:35][CH:36]([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl [(3R,4R)-1-benzyl-4-{[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]carbamate (4.76 g, 10 mmol), isoamyl bromide (1.2 eq), and K2CO3 (2.76 g, 20 mmol) in 50 mL of DMF was stirred overnight at 50° C. The mixture was diluted with H2O, extracted with EtOAc, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5→20% EtOAc in hexane to give the title product.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[N:44]=[C:43]([C:45]([OH:47])=[O:46])[CH:42]=[CH:41][CH:40]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:14]=[C:13]3[C:39]2[N:44]=[C:43]([C:45]([OH:47])=[O:46])[CH:42]=[CH:41][CH:40]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(C(=O)O)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (500 mg, 0.957 mmol) and 6-bromopicolinic acid (280 mg, 1.436 mmol, Sigma-Aldrich) in DME (10 mL)/water (2.5 mL) was added Na2CO3 (304 mg, 2.871 mmol) and Pd(PPh3)4 (111 mg, 0.096 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 518.2 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Sc2ccccc2)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-2-nitrotoluene (ABCR; 120 μl; 0.97 mmol), thiophenol (120 μl; 1.16 mmol) and K2CO3 (267 mg; 1.93 mmol) in DMSO (3 ml) was placed in a microwave vial and submitted to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was filtered, taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as a yellow solid.