Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:37])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@@H:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:17][NH:18]C(=O)OC(C)(C)C)=[O:14])[S:10][C:11]=1[Cl:12].C(O)(C(F)(F)F)=O.C(Cl)[Cl:46]>>[NH2:18][CH2:17][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([Cl:12])=[C:7]([C:6]2[N:5]([CH3:37])[N:4]=[CH:3][C:2]=2[Cl:46])[CH:8]=1)=[O:14])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: ClCCl
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl {(2S)-2-({[4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=1)CCC.O>C1(C)C=CC=CC=1.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:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (80 mg, 0.160 mmol), 5-(tributylstannyl)-3-vinylisothiazole (96 mg, 0.240 mmol), and tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.080 mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and were concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid, which was used without further purification (81.3 mg, 88%). ESI-MS m/z [M+H]+ calc'd for C28H36FN5O5S, 574. found, 574.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:21])[CH:13]=1)[C:6]([O:8]CC)=[O:7])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[O:21])[CH:13]=1)[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)OC(Cc1cccc(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.6 %

Procedure:
To 149 mg of Ethyl 2-isopropoxy-3-{3-[({[4-(trifluoromethyl)anilino]carbonyl}-oxy)methyl]phenyl}propanoate were added 4 ml of ethanol and 1.0 ml of 5N sodium hydroxide aqueous solution, and the mixture was stirred at room temperature for 20 hours. After the reaction solution was diluted with water, pH was adjusted to 5 with 5N hydrochloric acid, and the solution was diluted with ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography, to give 26 mg of the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:17]=1>ClCCl.CN(C)C=O>[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[O:9])[N:17]=1
Reactant: Nc1ccc(SCc2csc(N)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)Cc2csc(N)n2)cc1
Yield: 86.3 %

Procedure:
A solution of 3-chloroperbenzoic acid (4.9 g) in dichloromethane (100 ml) was dropwise added to a solution of 2-amino-4-(4-aminophenylthiomethyl)thiazole (5.1 g) in a mixture of dichloromethane (200 ml) and N,N-dimethylformamide (10 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 1.5 hours with stirring. The precipitates were collected by filtration, washed with ethyl acetate and dried in vacuo to give solid. The solid was recrystallized from ethanol to give 2-amino-4- (4-aminophenylsulfinylmethyl)thiazole (4.70 g, yield: 86.3%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=4[CH3:1])=[CH:16][CH:15]=3)=[O:14])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CC1=C(c2ccc(C(=O)O)cc2)CCCC1
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1
Yield: 91.9 %

Procedure:
4-(2-Methyl-cyclohex-1-en-1-yl)-benzoic acid of Step C (0.720 g, 3.33 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.674 g, 3.66 mmol) were reacted in the manner of Example 1, Step D. The title compound was purified by recrystallization from petroleum ether to afford white crystals (1.17 g), m.p. 119–120° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][CH:16]1[CH2:21][N:20]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH2:19][CH2:18][NH:17]1
Reactant: CC1CNCCN1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC1CN(c2ccc(F)cc2)CCN1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
Sodium-t-butoxide (4.1 g) was added to a solution of tir-tolylphosphine (0.638 g) and palladium acetate (0.319 g) in toluene (250 mL) under argon and the mixture was stirred for 20 minutes. 4-Fluoro-bromobenzene (5 g) and 2-methylpiperazine (2.85 g) were added and the mixture was heated at 110° C. for 7 hours, then allowed to cool to ambient temperature and keep at this temperature for 20 hours. The reaction mixture was filtered through Celite®, the filter cake was washed twice with dichloromethane (2×25 mL) and the filtrate was evaporated to dryness. The residue was chromatographed on silica eluting initially with dichloromethane and then with a mixture of dichloromethane, methanol and ammonium hydroxide (100:5:1) to give 2-methyl-4-(4-fluorophenyl)-piperazine, 2.5 g.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl:13]C1C=C(C(OCC)=O)NC=1C>>[Cl:13][C:4]1[CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: CCOC(=O)c1ccc(CC)[nH]1
Product: CCOC(=O)c1cc(Cl)c(CC)[nH]1

Procedure:
Title compound was synthesized from ethyl 5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 12) by an analogous method to Intermediate 9.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26](Cl)=[C:21]3[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([N:30]4[N:31]=[CH:32][CH:33]=[N:29]4)=[C:21]3[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]nn1
Reactant: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(-n3nccn3)ccnc12

Procedure:
Example 205 and 206. In a sealed tube -(4-benzoyl-piperazin-1-yl)-2-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione (30 mg, 0.076 mmol), 1H-1,2,3-triazole (160 mg, 2.3 mmol), Cu (0) (10 mg, 0.16 mmol) and K2CO3 (11 mg, 0.080 mmol) were heated at 160° C. for 16 h. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The residue was purified by preparative HPLC to provide 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) δ 8.79 (d, J=6.6 Hz, 1H), 8.79 (s, 1H), 8.48 (d, J=6.6 Hz, 1H), 8.40 (s, 2H), 7.48 (br s, 5H), 4.00-3.55 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.91 min (Column G); and 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) δ 8.97 (d, J=61.2 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.47 (br s, 5H), 4.00-3.45 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.90 min (Column G).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[O:1]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: OCCc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1O

Procedure:
2-Hydroxyethylphenol (XLVa) (15.2 g, 0.11 mol) and t-butyldimethylsilyl chloride (18.2 g, 0.121 mol) were placed together in DMF (120 mL; Aldrich Sure Seal). While the solution was being stirred, imidazole (16.5 g, 0.242 mol) was added portionwise (slightly exothermic). After stirring for 3 h at room temperature, EtOAc (200 mL) was added and the resultant solution was washed with water (3×200 mL) and brine (200 mL). The EtOAc layer was dried over anhydrous sodium sulfate, filtered and concentrated to leave a yellow oil which was purified by silica gel column chromatography (being eluted with 19:1 hexanes/EtOAc) to obtain 27.7 g (0.11 mol, Y: 100%) of the title compound as an oil; Rf: 0.40 (19:1 hexanes/EtOAc); 1H-NMR (CDCl3) δ ppm: 0.067 (6H, s, SiMe2), 0.893(9H, s, SitBu), 2.87 (2H, t, J=5 Hz, ArCH2), 3.91 (2H, t, J=5 Hz, CH2OSi), 6.80 (1H, dt, J=1.3, 7.4 Hz, 5'-H), 6.90 (1H, dd, J=1.2, 8 Hz, 2'-H), 7.00 (1H, dd, J=1,5, 7.3 Hz, 6'-H), 7.12 (1H, dt, J=1.6, 7.5 Hz, 4'-H), 8.29 (1H, s, OH, D2O exchanged); IR (film) 3300 (OH), 1616 cm-1 ; MS (FAB/NOBA) m/e: 253 (MH+), 237, 209.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[CH:16]=[N:15][C:14]([NH2:17])=[N:13][C:12]1=[O:18])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CC#N>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]1[CH:16]=[N:15][C:14]([N:17]=[CH:21][N:22]([CH3:24])[CH3:23])=[N:13][C:12]1=[O:18])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCc1cccc(CC)c1-n1cnc(N)nc1=O
Solvent: CC#N
Product: CCc1cccc(CC)c1-n1cnc(N=CN(C)C)nc1=O
Reaction time: 8 h

Procedure:
1-(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one (5.9 g, 20 mmo) is combined with 30 ml of CH3CN, none of the solid dissolves. To this is added 1.19 g (10 mmol) of N,N-dimethylformamide dimethylacetal. The solid dissolves within seconds. The reaction solution was stirred overnight.
Reaction SMILES: C1(CCC[CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:29]=3)[CH3:27])=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])C=CC=CC=1.[OH-:40].[Na+]>>[O:40]([CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: CC(=NOCCOc1ccc(CC(CCCc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Agent: [Na+]
Product: CC(=NOCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
Reaction and post-treatment were carried out according to Example 18 using 1.28 g of ethyl 2-phenoxy-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 20 and 7.00 ml of a 1N aqueous sodium hydroxide solution to obtain 1.13 g of the desired compound as a crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([NH:23][CH:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:42])[F:41])[C:25]([NH:27][C:28]([CH3:33])([C:30]([NH2:32])=[O:31])[CH3:29])=[O:26])=[O:22])[N:9]=2)=[CH:4][CH:3]=1>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([NH:23][CH:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:42])[F:43])[C:25]([NH:27][C:28]([CH3:29])([C:30]([NH2:32])=[O:31])[CH3:33])=[O:26])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F)C(N)=O
Agent: [Pt]
Solvent: CO
Product: CC(C)(NC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O)c1ccccc1C(F)(F)F)C(N)=O

Procedure:
A solution of 25 mg (39 μmol) of the compound of Example 31 in 10 ml of methanol was hydrogenated in an H-Cube fitted with a platinum cartridge (5% Pt/C) (continuous-flow hydrogenation apparatus from Thales Nano, Budapest, Model HC-2-SS) at a flow rate of 1 ml/min, at 60° C. and under hydrogen at standard pressure. The resulting solution was freed from methanol on a rotary evaporator, and the residue was dissolved in 2 ml of acetonitrile and purified by preparative HPLC [Method 7]. This gave 8 mg (32% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[CH:16]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 87.5 %

Procedure:
Following the procedure described for Example 1(A), Step B, [4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester (4.84 g, 9.37 mmol) was reduced in EtOH (150 mL) for 3 hours at 80° C. The residue was dissolved in EtOAc and was washed with aqueous NH4Cl (1×) and brine (1×). The organic solution was dried (Na2SO4), filtered and concentrated to provide 4.26 g of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester. 1H NMR (DMSO-d6), δ 7.65 (d, 1H), 7.53-7.38 (m, 7H), 7.27 (m, 1H), 7.18 (m, 2H), 6.98 (m, 1H), 6.89 (m, 2H), 4.75 (d, 1H), 4.43 (d, 1H), 3.82 (t, 1H), 3.59 (m, 2H), 1.22 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]1[CH2:19][C:18](=[O:20])[C:17]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]1[CH2:19][C:18](=[O:20])[CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2cc(F)ccc2OCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC(c2cc(F)ccc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[2-(benzyloxy)-5-fluorophenyl]-2,2-dichlorocyclobutanone (C18) (1.4 g, 4.14 mmol) and zinc dust (1.08 g, 16.5 mmol) in acetic acid (25 mL) was stirred at room temperature for 2 hours and then at 100° C. for 1.25 hours. The mixture was filtered through Celite, and the filtrate was washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptanes) afforded the title compound as a colorless oil. Yield: 674 mg, 2.49 mmol, 60%. LCMS m/z 179.4 [M−(C7H7)]. 1H NMR (400 MHz, CDCl3) δ 3.22-3.31 (m, 2H), 3.36-3.46 (m, 2H), 3.75-3.85 (m, 1H), 5.08 (s, 2H), 6.87-6.95 (m, 2H), 6.99 (dd, J=9.2, 2.7 Hz, 1H), 7.33-7.44 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2.6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (17.73 g) and water (125 ml) is stirred at about 80° C. for 24 hours. Excess 2-chloroacrylonitrile is distilled off by raising the external temperature to about 130° C. The semi-solid mixture is cooled to about 40° C. and the suspension is treated with cyclohexane (50 ml), brought to about 20° C. and stirred for about 2 hours. The product is isolated by filtration, washed with cyclohexane (75 ml) and then with water (50 ml). The moist product is mixed with water (100 ml), the suspension is filtered and the product is washed with water (50 ml) and dried in vacuo at about 60° C. Yield: 38.04 g=86%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CN(C)C=O.CCCCCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH3:19])=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=c1cc(CO)[nH]cc1OCc1ccc(Cl)cc1
Solvent: CO
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(CO)ncc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Chloro-benzyloxy)-2-hydroxymethyl-1H-pyridin-4-one (639, 1.06 g, 3.99 mmol) was dissolved in methanol (8.5 mL) and N,N-dimethylformamide (46 mL). Trimethylsilyldiazomethane in hexane (2.00 M, 3.99 mL) was added. The reaction was stirred at room temperature overnight, then additional trimethylsilyldiazomethane in hexane (2.00 M, 3.99 mL) was added. The reaction was stirred at room temperature for 2 days. The mixture was adsorbed onto silica and purified by silica gel chromatography, methanol:dichloromethane to provide the compound (640, 798 mg, 72%). MS (ESI) [M−H+]+=280.4, 282.4.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1
Reactant: OCCO
Reactant: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)OCCO
Yield: 78.3 %

Procedure:
To a mixture of 6-(4-nitrophenoxy)hexanoic acid 53 (50 g, 197.62 mmol) and ethylene glycol (200 ml) was passed dry HCl gas for one hr. During HCl gas bubbling the temp. rose to 60° C. The crude reaction mass was poured onto ice (1 Kg), extracted into ethyl acetate, washed with water (2×250 ml), dried over sodium sulphate and distilled to get crude 54, which was purified by column chromatography on silica gel using benzene as eluant to get pure 54 (46 g, 78.3%) as a light yellow syrup.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (19%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-piperidinecarboxylic acid ethyl ester (25.0 g) and 3-nitrophenylboronic acid (31.9 g) in dichloromethane (1.0 L) are added pyridine (64.8 ml), anhydrous copper (II) acetate (28.9 g) and Molecular Sieves 4 Å (500 g), and the mixture was stirred at 25° C. for 3 days. The reaction solution is poured into 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent is evaporated under reduced pressure to give the title compound.
Reaction SMILES: ClC(OCC)=O.[C:7](=[O:32])([O:20][C:21]1[C:26](F)=[C:25](F)[C:24](F)=C(F)C=1F)[O:8][C:9]1C(F)=C(F)C(F)=C(F)C=1F>>[C:7]1(=[O:32])[O:8][CH2:9][CH2:24][CH2:25][CH2:26][CH2:21][O:20]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCOC(=O)Cl
Product: O=C1OCCCCCO1

Procedure:
Cyclizations of the above diols were also attempted using ethyl chloroformate, and bis(pentafluorophenyl) carbonate (PFC). Table 7 summarizes the results.