Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)[CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)C>CCOCC>[Br:23][C:21]1[CH:22]=[C:17]([CH:16]=[CH:15][CH2:14][OH:13])[CH:18]=[N:19][CH:20]=1
Reactant: CCOC(=O)C=Cc1cncc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: OCC=Cc1cncc(Br)c1
Yield: 84.1 %

Procedure:
A solution of diisobutylaluminum hydride (DIBAL-H, 8.02 mls, 1.54M in toluene) in ether (50 mls) is cooled to -78° C. under N2. A solution of 3-(5-bromo-3-pyridinyl)-2-propenoic acid ethyl ester [see Nishikawa, Y., et al.(1989) J. Med. Chem. 32, 583-593] (1.54 gms, 6.00 mmol) in ether (50 mls) is added. After one hour the dry ice/acetone bath is removed and the mixture is diluted with methylene chloride, dried over Na2SO4, evaporated and chromatographed (1:1 ethyl acetate:hexane followed by 2:1 ethyl acetate:hexane) to yield 1.08 gms of an oil (84%). 1H NMR (DMSO, 300 MHz) δ8.60 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 6.60 (m, 2H), 5.00 (s, 1), and 4.10 (d, J=3.8 Hz, 2H).
Reaction SMILES: O.O.[C:3]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[CH2:12]([CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C>[CH2:12]([C:19]1[C:20](=[O:21])[O:4][C:3]2[CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[C:5]=2[C:25]=1[CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol dihydrate (20 g) and ethyl 2-benzylaceto-acetate (27.5 ml) in ethanol (320 ml) was treated with dry HCl at 0° C. for five hours and the solution was kept at that temperature overnight. The yellow solution was concentrated and triturated with water, the solids filtered, washed with water and dried. The resulting hydrate was thrice evaporated to dryness from toluene, triturated with pethroleum ether (bp. 40-60° C.) and filtered. Yield 33,4 g (96%). Melting point 258-260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:37])([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 110 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809 μmol) in dichloromethane (15 mL) was added triethylamine (250 μL, 1.78 mmol) and 2-nitrobenzoyl chloride (240 μL, 1.78 mmol). The solution was stirred at room temperature for 110 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.23 min, MH+ 459].
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=O)[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22]([N:65]2[CH2:66][CH2:67][CH:62]([OH:61])[CH2:63][CH2:64]2)=[O:24])=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: OC1CCNCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCC(O)CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 4-Hydroxypiperidine (43.9 mg, 434 μmol, 5 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (51 mg, 98% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])=[CH:17][CH:16]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCc1ccc(F)cc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 4-fluorophenethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. δH (CD3OD): 2.93 (2H, t), 3.60 (2H, t), 6.97-7.04 (3H, m), 7.24-7.30 (2H, m), 7.65 (1H, s), 8.56 (1H, s); m/z (ES+) 318 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:18]=[N:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:26]([Mg]Br)=[CH2:27].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH:26]=[CH2:27])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)N=CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Reactant: C=C[Mg]Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(NS(=O)C(C)(C)C)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
Under argon, 2.00 g (5.44 mmol) of 2-methyl-propane-2-sulfinic acid 8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylmethyleneamide (105) were dissolved in 27 mL of absolute tetrahydrofuran. Then, 5.99 mL (5.99 mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were added dropwise at 0° C. and the reaction mixture was stirred for 17 h at room temperature. Another 3 mL (3.00 mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were added and the mixture stirred for 20 h at room temperature. The reaction mixture was cooled to 0° C. and 15 mL of saturated aqueous sodium sulphate solution were added. The suspension was filtered over celite, the organic layer was dried over magnesium sulphate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to yield 1.09 g of (106). Rt=0.96 min (Method 18). Detected mass: 396.4 (M+H+).
Reaction SMILES: [Na].C([C:5]1[C:6](CC(C)C)=[C:7]([C:18]([O:20]C)=[O:19])[C:8](C(F)F)=[N:9][C:10]=1C(F)(F)F)(=O)C.N(OCCC(C)C)=O>CO>[N:9]1[CH:10]=[CH:5][CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C)=O)c1CC(C)C
Agent: CC(C)CCON=O
Agent: [Na]
Solvent: CO
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
This example illustrates the preparation of Compound 101, an example of the formation of the heterocycle by cycloaddition reaction. Sodium (7.87 g, 0.35 mol) was cautiously added in portions to 250 mL methanol under nitrogen. Methyl 5-acetyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (20 g, 0,057 mol) was added at 25° C., followed by dropwise addition of isoamyl nitrite (33.15 g, 0.283 mol). The mixture was stirred overnight at 25° C., then quenched with ice/concentrated HCl slush, and extracted with ether. The combined ether layers were washed with saturated sodium bicarbonate and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by HPLC with 10% ethyl acetate-hexane to give 22 g (99%) of 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-((hydroxyimino)acetyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester, as a yellow solid. m.p. 84°-86° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25](O)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][NH2:36]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([NH:36][CH3:35])=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1C

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 9 starting from 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (Step 2) and methylamine in THF solution (2.0 M). LCMS (M+H)+: m/z=475.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]2[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][N:20]=[CH:21][C:16]2=[N:15][N:14]=1.[BH4-].[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]2[CH:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][NH:20][CH2:21][C:16]2=[N:15][N:14]=1
Reactant: COc1cc(Br)c(Nc2nnc3cncc(-c4ccccc4)n23)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Br)c(Nc2nnc3n2C(c2ccccc2)CNC3)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
To a stirring suspension of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine (0.2 g, 3.7 mmol) in a mixture of THF (20 mL) and TFA (1 mL) at 0° C. was added sodium borohydride (20 mg, 4.0 mmol). The reaction mixture was stirred 15 minutes at room temperature, thane quenched by addition of 10% aqueous HCl. The resulting mixture was heated to reflux for 10 minutes, then cooled and made basic by addition of 1M aqueous NaOH. The mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 0.18 g of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine, MS (M+H)=431.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C(OCC1CO1)C1CO1
Reaction time: 1.5 h

Procedure:
The reaction product of (a), 1 liter of epichlorohydrin and 20 gm of benzyltrimethylammonium chloride (BTMAC) dissolved in 12 ml of water are charged to a 2 liter 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, thermoregulator, condenser, Dean-Stark Trap and dropping funnel. The mixture is then heated to about 50° to 55° C. at high vacuum of 70 torr with stirring resulting in a vigorous reflux of the epichlorohydrin. 109 gm of NaOH (50% solution) is slowly added to the mixture over a period of 2 hours. The water/epichlorohydrin mixture is removed by distillation as soon as the azeotrope is formed. Upon completion of the addition, the epichlorohydrin is returned to the reaction mixture and the reaction is allowed to continue for an additional 1.5 hours. The reaction mixture is then cooled to room temperture and washed with 300 ml of ice water and separated. The organic layer is then washed with another 300 ml of water and the pH adjusted to about 5-6 using 10% aqueous acetic acid. The organic layer is then washed a third time with 300 ml of water and separated. The epichlorohydrin is then removed by distillation at reduced pressure (from 70 to 2 torr). The final distillation condition about less than 5 torr/110° C. The distillation is continued until no volatile could be distilled to ensure the complete removal of the epichlorohydrin. The yield is 330 gm. The epoxy value is 0.306 eq/100 g and the viscosity is 1310 cps at 25° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19]3[N:18]=[C:17]([CH3:16])[CH:22]=[CH:21][N:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cc1ccnc(S(C)(=O)=O)n1
Product: Cc1ccnc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
6-Chloro-N-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-methyl-2-methylsulfonylpyrimidine in a similar manner as described above to give 6 mg (7% yield) of a yellow solid. 1H-NMR (CDCl3): δ 9.05 (s, 1H), 8.23 (d, 1H), 7.45 (m, 1H), 7.17 (d, 1H), 7.07 (dd, 1H), 6.52 (d, 1H), 5.36 (m, 1H), 5.20 (m, 1H), 2.70 (m, 2H), 2.38 (s, 3H), 2.29 (m, 1H), 2.02-1.85 (m, 3H); MS m/z 311 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[CH3:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:11]=2[CH3:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C)c21
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(C)c21
Reaction time: 18 h
Yield: 11.5 %

Procedure:
A mixture of 1-ethyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (350 mg), anhydrous piperazine (450 mg) in anhydrous DMSO (4 ml) was stirred at 50° to 72° C. for 18 hours. After the reacting mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting chloroform-methanol-concentrated aqueous ammonia (20:6:1) to give the title compound (50 mg) as pale yellow flakes, mp 153°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=1)=[O:21]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2cccnc2)cc1C=O
Product: COc1cc(OC)c(-c2cccnc2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 51 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-pyridin-3-yl-benzaldehyde (Ex-104A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 51% yield, mp 253–255° C. 1H-NMR (DMSO-d6) δ 8.69 (d, J=1 Hz, 1H), 8.50 (d, J=4 Hz, 1H), 8.25 (d, J=9 Hz, 2H), 8.08 (d, J=15 Hz, 1H), 8.02 (s, 1H), 7.84–7.94 (m, 4H), 7.51 (s, 2H), 7.40–7.44 (m, 1H), 6.82 (s, 1H), 3.98 (s, 3H), 3.88 (s, 3H). MS m/z=424([M]+, 45%), 393 (100%). HMRS (EI) calcd. for C22H20N2O5S: 424.1093; found 424.1100.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[CH:31][N:30]([CH3:33])[C:29]=2[CH:34]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:33][N:30]1[C:29]2[CH:34]=[C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=[CH:27][C:28]=2[N:32]=[CH:31]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Cn1cnc2ccc(N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cnc2ccc(N/C(=C3\C(=O)Nc4ccccc43)c3ccccc3)cc21

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 2 equivalents of 6-amino-1-methyl-benzimidazole, melting point 163-165° C., in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.C([N:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][C:35](O)=[O:36])C.O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH2:38]([N:33]1[CH2:34][C:35](=[O:36])[N:9]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[C:8]1=[O:30])[CH2:39][CH2:40][CH3:41]
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CCCCN(CC)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: CCCCN1CC(=O)N(c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)C1=O

Procedure:
A mixture of 24 parts of phenyl[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 15.9 parts of ethyl N-butylglycine, 2 parts of N,N-dimethyl-4-pyridinamine and 200 parts of 1,4-dioxane was stirred and refluxed overnight. Then water was added and stirring was continued for a while. The reaction mixture was cooled, poured onto water and the whole was stirred. The precipitated product was filtered off, washed with water and dissolved in 150 parts of trichloromethane. This solution was stirred for 30 minutes with 3 parts of silica gel. The latter was filtered off and the filtrate was evaporated. The residue was crystallized from butanol. The product was filtered off and dried in vacuo at 60° C., yielding 2.3 parts of 1-butyl-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 183.7° C. (39).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CBr

Procedure:
A mixture of 5-fluoro-N,N,2-trimethylbenzenesulfonamide (5.20 g, 24.0 mmol) and N-bromosuccinimide (4.69 g, 26.4 mmol) in dry CCl4 (100 mL) was refluxed overnight under nitrogen. Cooled the reaction and filtered off the succinimide salts by vacuum filtration, washing with CCl4. The concentrated filtrate was dissolved in a minimal amount of ethyl acetate and purified on an Isco column (110 g silica) running a 0 to 20% EtOAc/Hexane gradient over 40 minutes. The collected fractions were concentrated in vacuo to afford the desired material as a yellow oil in a ratio of 3.5:1 with the starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:38][CH:39]1[CH2:41][O:40]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:38][CH:39]1[CH2:41][O:40]1)[CH:7]=[C:6]2[C:12]1[N:24]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:15]2=[N:16][CH:17]=[C:18]3[CH:22]=[N:21][N:20]([CH3:23])[C:19]3=[C:14]2[CH:13]=1
Reactant: ClCC1CO1
Reactant: COc1ccc2[nH]cc(-c3cc4c5c(cnc4n3S(=O)(=O)c3ccc(C)cc3)cnn5C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a reaction flask was added 7-(5-methoxy-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.100 g, 0.212 mmol; Preparation #P.1.1), DMF (3 mL) and 60 wt % NaH (0.010 g, 0.254 mmol) and 2-(chloromethyl)oxirane (0.026 g, 0.276 mmol). The mixture was stirred for about 2 h at rt. The mixture was concentrated in vacuo to provide 7-(5-methoxy-1-(oxiran-2-ylmethyl)-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (100% yield assumed and carried forward to Step B): LC/MS (Table 2, Method c) Rt=1.49 min; MS m/z 528 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH:26]2[CH2:31][O:30]C(C3C=CC=CC=3)[O:28][CH2:27]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(OC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)oxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step iv) (220 mg) in methanol (5 ml)/water (0.1 ml) was added pyridinium p-toluenesulfonate (20 mg) and the mixture was stirred at ambient temperature for 1.5 hour, then at reflux for 20 hour. The reaction mixture was evaporated, suspended in water and extracted with ethyl acetate (×2). The combined organic layers were dried with magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using a 98:2 mixture of methylene chloride and methanol as eluent to give the title compound as a white solid. Yield: 120 mg MS: APCI(+ve) 463, [M+H+]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Li]CCCC.[B:24](OC)([O:27]C)[O:25]C.Cl>>[Si:11]([O:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([B:24]([OH:27])[OH:25])=[CH:3][CH:4]=1)[CH3:18])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: COB(OC)OC
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Product: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of 73C (100 mg in 2 mL dry THF, 0.3 mmol) at −78° C. was added n-BuLi (1.6 M, 0.2 mL, 0.32 mmol), followed by B(OMe)3 (0.1 mL, 0.9 mmol). The solution was stirred at −78° C. for 2 h. 1N HCl (4 mL) was added, and stirred 30 min. The mixture was extracted with EtOAc (3×20 mL). The organic layer washed by brine, dried (Na2SO4). Purification through ISCO (0-80% EtOAc in hexanes) gives 73D (37 mg, 40%). 1H NMR (400 MHz, Chloroform-d) δ ppm −0.03 (d, J=3.52 Hz, 6 H) 0.84-0.89 (m, 9 H) 1.33 (d, J=7.03 Hz, 3H) 2.92-3.06 (m, 1 H) 3.62-3.79 (m, 2 H) 7.36 (d, J=7.91 Hz, 2 H) 8.16 (d, J=7.91 Hz, 2 H)