Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:38])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:17]4=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.C(OC)(OC)OC.[CH3:46][N:47]1[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.ClCCCl>[Cl:38][C:6]1[C:5]([CH:3]2[CH2:4][N:1]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:2]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:30]2[CH2:31][CH2:32]2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CNC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CN1CCC(N2CC(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)C2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83.3 %

Procedure:
To a solution of 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (53 mg, 0.084 mmol) in methanol (1.2 ml) was added trimethyl orthoformate (0.6 mL, 5.43 mmol), 1-methylpiperidin-4-one (0.1 ml, 0.866 mmol) and acetic acid (10 μL, 0.175 mmol). The mixture was stirred at RT for 40 min and then sodium cyanoborohydride (42.0 mg, 0.669 mmol) was added. After 4 h, the reaction mixture was partitioned between EtOAc and dilute aq. NaHCO3 solution. The organic layer was washed with brine, and dried over Na2SO4. Removal of the solvent left the crude intermediate. To this was added DCE (1 ml), anisole (0.046 ml, 0.418 mmol), and TFA (0.5 ml). The resulting mixture was heated at 50° C. for 3 h. the solvents were removed and the crude material was purified by prep-HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml permin, 20-100% B, over 20 min). The HPLC fractions containing the product were applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and dichloromethane (1:1). Removal of the solvents afforded 2-((2-chloro-5-cyano-3-(1-(1-methylpiperidin-4-yl)azetidin-3-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35.2 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.O.NN.O.CCCCCC>C(O)C.[Ni].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 4-fluoro-2-methoxynitrobenzene (4.2 g) in ethanol (50 ml) was added Raney-nickel (0.4 g) at room temperature. To this solution was added dropwise hydrazine monohydrate (6 ml) under ice-cooling. This reaction mixture was stirred at room temperature for 1 hr and passed through Celite. The solvent was evaporated to give an oil. The oil was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give a brown oil. The oil was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) to give the title compound (3.1 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl:23][C:24](Cl)([Cl:28])[CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:4]([Cl:9])[CH:5]=1
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cc(O)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)CC1
Yield: 24.1 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step C, by the reaction of 2.8 grams (0.008 mole) of tert-butyl 4-(2,6-dichloro-4-hydroxyphenyl)piperazinecarboxylate, 2.2 grams (0.012 mole) of 1,1,1,3-tetrachloropropane and 1.7 grams (0.012 mole) of potassium carbonate in 75 mL of DMF. The crude reaction product was purified with column chromatography on silica gel using 50% hexane in methylene chloride and finally 100% methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.88 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional material for the next reactive step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([NH2:23])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:24][C@H:25]1[CH2:26][N:27]([CH2:18][C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]([C:21]([NH2:23])=[O:22])[C:11]3=[O:20])[CH2:28][C@@H:29]([CH3:31])[O:30]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C=O)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccc3c(c2)c(=O)c(C(N)=O)cn3-c2ccc(F)cc2)C[C@H](C)O1
Reaction time: 16 h
Yield: 38.2 %

Procedure:
A solution of compound G (10 mg, 0.032 mmol), cis-2,6-dimethylmorpholine (5 μL, 0.039 mmol), and acetic acid (4.6 μL, 0.081 mmol) in dichloromethane (1 mL) were stirred for one hour. To this mixture was added sodium triacetoxyborohydride (10.2 mg, 0.048 mmol). After 16 hours, the reaction was concentrated to dryness. Purification by reverse phase HPLC afforded 5 mg (38%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J=4.4 Hz, 1H), 8.55 (s, 1H), 8.26 (d, J=1.8 Hz, 1H), 7.77-7.73 (m, 2H), 7.65 (dd, J=8.7, 2 Hz, 1H), 7.59 (d, J=4.4 Hz, 1H), 7.52 (t, J=8.68, 8.76, 2H), 7.03 (d, J=8.68, 1H), 3.57-3.52 (m, 4H), 2.65 (d, J=10.2 Hz, 2H), 1.01 (d, J=6.3 Hz, 6H); ES-MS [M+1]+: 410.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.[O:17]1CCOCC1>[OH-].[Na+].O>[OH:17][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(CO)cc(C(C)(C)C)n1
Temperature: 25 °C

Procedure:
A heterogeneous solution of 4-bromomethyl-2,6-di-t-butylpyridine (Compound A, 1.743 g, 82% purity) in 20 ml of 12% NaOH in water and 10 ml of 1,4-dioxane was refluxed for 12 hours. The solution spontaneously separated into two layers as it cooled to room temperature. The upper layer was separated and ethyl acetate was added. This organic layer was then washed with brine, water and dried over MgSO4. The desired product was purified by column chromatography (ethyl acetate/hexane 1/9) to give a white solid. 1H NMR δ 7.09 (s, 2H),. 4.67 (d, J=4.4 Hz, 2H), 2.3 (b, 1H), 1.36 (s, 18H).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:56]2[N:57]=[C:58]([NH:61][C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[S:59][CH:60]=2)\[C:25]([NH:27][CH:28]2[C:54](=[O:55])[N:30]3[C:31]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:32]([CH2:36]Cl)[CH2:33][S:34](=[O:35])[C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:81].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:56]2[N:57]=[C:58]([NH:61][C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[S:59][CH:60]=2)\[C:25]([NH:27][CH:28]2[C:54](=[O:55])[N:30]3[C:31]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:32]([CH2:36][I:81])[CH2:33][S:34](=[O:35])[C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CI)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The residue obtained in (B) was dissolved in 40 ml of acetone, and 990 mg (6.6 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. Then, 120 ml of ethyl acetate and 20 ml of a 5% sodium thiosulfate aqueous solution were added to the reaction solution for liquid separation. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The concentrated residue was subjected to silica gel flush column chromatography (ethyl acetate/n-hexane=1/2). The fraction containing the desired product was collected, and concentrated under reduced pressure, and isopropyl ether was added to the residue to obtain 2.92 g of a powder of the above identified compound (yield from A: 80.3%).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[OH:12][NH3+:13].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:13][OH:12])[NH2:5]
Reactant: N#Cc1cccc(F)c1F
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.0 g (35.2 mmol) of 2,3-difluorobenzonitrile were initially charged in 43 ml of ethanol, and a solution of 3.7 g (52.8 mmol) of hydroxylammonium chloride and 5.9 ml (4.3 g, 42.3 mmol) of triethylamine was added at RT. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 5.7 g (94% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].I[CH2:18]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]1[C:3]2[C:4](=[O:5])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:18][O:1][C:2]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1O)c1ccccc1O
Reactant: ICI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OCOc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1 g, 49 mmol) was dissolved in dry N,N-dimethylformamide (180 ml). Dried finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added and the mixture was heated at 105° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate was collected by filtration after 0.5 h, washed with water on the filter and dissolved in a mixture of ethanol (80 ml) and 4 N sodium hydroxide (20 ml). The solution was stirred at reflux temperature for 1 h, cooled and diluted with water (300 ml). The formed crystalline precipitate was filtered off, washed with water (50 ml) and dried in vacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-12-one as a solid (9.5 g, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
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: O
Solvent: C1COCCO1
Product: CC(C)Cn1nc2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccc(C(F)(F)F)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-trifluoromethylphenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 g, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 12 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (15 mg, 0.038 mmol) as a yellow solid. MS: [M+H]+=394.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+:39].O>C(O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][CH2:24][C:25]([O-:27])=[O:26])[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[Na+:39]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])CCn1ccc2c(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-{5-[2-(trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanoate (D64) (15 mg, 0.31 mmol) was dissolved in ethanol (50 ml) by warming to 40° C. for 10 minutes then 2N sodium hydroxide (4 ml, 8 mmol) was added followed by water (8 ml). The solution was left standing for 1 hour. Evaporated off the ethanol and filtered off the off-white solid. Mass of title compound as a beige obtained on drying was 42 mg. δH (400 MHz, methanol-d4) 2.69 (2H, t), 4.53 (2H, t), 7.17-7.18 (1H, m), 7.32-7.40 (3H, m), 7.46-4.49 (4H, m), 7.66 (1H, d), 7.75 (1H, d), 8.02 (1H, d), 8.53 (1H, dd), 8.63 (1H, d). MS (ES) C26H18F3N3O3 requires 477; found 478 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:28](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][S:22][C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:39][CH3:40].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:28][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][S:22][C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:39][CH3:40]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CSc4cccs4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CSc4cccs4)ccnc3[nH]1)cn2C
Yield: 98.4 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.110 g of 5,6-dimethoxy-1-methyl-3-[4-(thiophen-2-ylsulfanylmethyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-pyrrolo[3,2-b]pyridine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 0.8 cm3 of 5N potassium hydroxide. 0.080 g of 5,6-dimethoxy-1-methyl-3-[4-(thiophen-2-ylsulfanylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-pyrrolo[3,2-b]pyridine is obtained with the following characteristics:
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][C:9]([Cl:13])=[CH:10][C:11]=1[Br:12].[Br:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[Br:14][C:15]1[C:16]([C:7]2[S:8][C:9]([Cl:13])=[CH:10][C:11]=2[Br:12])=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Clc1cc(Br)c(Br)s1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: C1CCOC1
Product: Clc1ncc(Br)c(-c2sc(Cl)cc2Br)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
nBuLi (1.1 mL, 1.6 M solution in hexane, 1.8 mmol) was added to a stirred solution of 2,3-dibromo-5-chlorothiophene (0.50 g, 1.8 mmol) in 10 mL of THF at −78° C. The solution was stirred for 10 min at −78° C. before 0.35 g (1.8 mmol) of 5-bromo-2-chloropyrimidine was added. The reaction solution was stirred for 30 min at −78° C., then quenched by addition of 1 mL of AcOH in 4 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.82 g, 3.6 mmol) was added and the reaction mixture warmed to 0° C. and stirred for 10 min. The reaction mixture was then poured into 50 mL of a 0.5 M solution of sodium ascorbate and diluted with 100 mL of a 1 M aqueous solution of Na2CO3. The aqueous solution was extracted four times with CH2Cl2 and the combined organic extracts dried over MgSO4, filtered and concentrated to give the crude product which was purified by flash chromatography eluting with a linear gradient of 50% EtOAc in hexane to neat EtOAc, then to 20% MeOH in EtOAc to deliver the title compound. MS (M+H)+ 389.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([O:24]C)=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.COC.O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([OH:24])=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: COc1ccc(-c2nnc(N)nc2-c2ccccc2)cc1NC(C)=O
Agent: COC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nnc(N)nc2-c2ccccc2)ccc1O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide was prepared by O-demethylation of N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.05 g, 0.15 mmol; vide supra). The methyl ether was dissolved in DCM (5 mL), cooled to −78° C. and treated with borontribromide (5.25 mmol, 1.32 g). The resulting mixture was gradually warmed to RT then stirred at this temperature for a further 16 hours. The mixture was poured into water (15 mL) and extracted with DCM (3×15 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuum and purified by gradient flash chromatography, eluting with 30% ethyl acetate in hexane to afford the target compound (0.30 g, 85%).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[Cl:8][C:9]([SH:12])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:8][C:9]1[S:12][N:5]=[C:4]([CH:3]([CH3:7])[CH3:2])[N:6]=1
Reactant: CC(C)C(=N)N
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nsc(Cl)n1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 2-methylpropanimidamide hydrochloride (2.00 g, 16.3 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.22 g (46.2%) of the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>C(Cl)Cl>[CH3:11][S:10][C:8]1[N:9]=[C:5]2[CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:1][C:16](=[O:17])[N:6]2[N:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1nc(Cc2ccccc2N)n[nH]1
Solvent: ClCCl
Product: CSc1nc2n(n1)C(=O)Nc1ccccc1C2

Procedure:
A mixture of 7 g of 3-(o-aminobenzyl)-5-methylmercapto-1,2,4-triazole, 5.26 g of 1,1'-carbonyldiimidazole and 179 ml of methylene chloride is heated at reflux overnight. Most of the solvent is removed in vacuo, the solids are filtered and washed with small amount of methylene chloride to give 2-methylmercapto-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine-5(6H)-one, m.p. 250°-252° (intermediate 5/b).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:37])[C:21]3[S:34][C:33]([CH2:35]Cl)=[CH:32][C:22]=3[N:23]([CH2:25][C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]([OH:49])[CH2:46][NH:47][CH3:48].O>CN(C=O)C>[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:37])[C:21]3[S:34][C:33]([CH2:35][N:47]([CH2:46][CH:45]([C:41]4[O:40][CH:44]=[CH:43][CH:42]=4)[OH:49])[CH3:48])=[CH:32][C:22]=3[N:23]([CH2:25][C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1ccco1
Reactant: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CN(C)CC(O)c3ccco3)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (34 μL, 0.19 mmol) was added to a mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (60 mg, 0.13 mmol) and 1-(2-furyl)-2-(methylamino)ethanol (27 mg, 0.19 mmol) in DMF (2.0 mL). The mixture was shaken at 60° C. for 3 hrs. The reaction was cooled to room temperature before the addition of water (5 mL). The resulting ppt was collected by filtration and washed with water. After drying in vacuo, the title compound was obtained as a pale yellow solid (41 mg).