Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH:18]1([CH2:23][C@@H:24]([C:33](F)=[O:34])[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(=O)C.[Cl-].[NH4+]>ClCCl>[CH:18]1([CH2:23][C@H:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:33]([N:1]2[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]=[N:2]2)=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)F
Reactant: O=C(O)C1CC=NN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
To a solution of 4,5-dihydro-1H-pyrazole-5-carboxylic acid (1.44 g, 8.8 mmol) in dichloromethane (DCM) (62 ml) at 0° C. was added Hunig's base (9.25 ml, 53.0 mmol) followed by 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-fluoro-4-oxobutanoate (3.8 g, 8.8 mmol) in 10 mL DCM. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was then cooled to 0° C. and acetic acid (2.5 ml, 44.1 mmol) was added, followed by sat. aq ammonium chloride (15 mL). The phases were separated and the aqueous phase was extracted once with DCM (20 mL). The combined organics were washed with brine (15 mL), dried over sodium sulfate, and concentrated to yield a yellow oil. This crude product was purified by Combiflash automated silica gel chromatography (0-100% EtOAc in hex) to afford 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (1.78 g, 5.05 mmol, 57% yield) as a clear oil. MS: 353 ([M+H]+).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(C)(=O)=O)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
Under a nitrogen atmosphere, methane sulfonic anhydride (550 mg) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (757 mg, 2.875 mmol), triethylamine (520 μL) and chloroform (11 mL). The reaction mixture was allowed to stir at ambient temperature for about 3 hours. The reaction mixture was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to provide crude product as a light yellow oil. The oil was purified by column chromatography (10 g of silica gel eluting with 2% methanol in chloroform containing 0.5 % triethylamine). The fractions containing product were combined and concentrated under reduced pressure. The residue was purified using Method A described above to provide 0.2753 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}methanesulfonamide.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[F:8][CH:9]([F:43])[C:10]([NH:12][C@H:13]([CH2:41][F:42])[C@@H:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1)[OH:15])=[O:11].N1C=CC=CC=1.C1COCC1.[CH2:55]([O:62][P:63]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)N(C(C)C)C(C)C)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.OO.O.S(=O)(=O)(O)[O-].[Na+]>O>[CH2:72]([O:71][P:63]([O:15][C@H:14]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH3:29])=[N:26][CH:27]=2)=[CH:20][CH:21]=1)[C@H:13]([NH:12][C:10](=[O:11])[CH:9]([F:8])[F:43])[CH2:41][F:42])([O:62][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:4])[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@@H](OP(=O)(OCc3ccccc3)OCc3ccccc3)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (51.6 μL) is added to the product of step 3, Example 95A (0.168 g, 0.335 mmol) and pyridine (54.2 μL, 0.67 mmol) in THF (4.4 mL, 54 mmol) at 0° C. After 5 minutes, bis(benzyloxy)(diisopropylamino)phosphine (0.219 mL, 0.586 mmol) is added. After allowing to warm to room temperature the mixture is stirred for 1 hour. 30% hydrogen peroxide/water (30:70, 60 μL, 0.586 mmol) is added. After 1 hour sodium bisulfate (4 mL) is added and water (10 mL) is added. The reaction mixture is extracted with ethylacetate (2×15 mL). The combined organics are dried over MgSO4, filtered and evaporated to give the crude product, which is purified by silica chromatography eluting from 25% ethylacetate/heptanes to neat ethylacetate to give the title product (241 mg): m/z: 761.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH:14]=[CH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC=CC(=O)C2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2CCCC(=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
5-(3,4-Dimethoxyphenyl)-2-cyclohexen-1-one (6.76 g) was dissolved in ethanol (100 ml), and 10% palladium-carbon (684 mg) was added thereto. After substituting the reaction vessel with hydrogen gas, hydrogen addition was effected for 30 minutes at normal pressure and room temperature. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce an oily substance which was dissolved in ethyl acetate (50 ml), and then 4 N HCl-ethyl acetate solution (2 ml) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to produce crude crystals which were then washed with n-hexane to give 6.72 g of 3-(3,4-dimethoxyphenyl)cyclohexanone (98.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[NH:13][C:12](=O)[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36]CCl>>[Cl:36][C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14](=[O:15])[N:13]=1
Reactant: ClCCl
Reactant: O=c1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=c1nc(Cl)cnn1-c1cc(Cl)cc(Cl)c1

Procedure:
In 30 ml of dichloromethane suspended with 1.00 g of 2-(3,5-dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione followed by addition of 2-fold morlar each of carbone tetrachloride and triphenylphosphine and refluxed for 12 hours. After the completion of the reaction, the resulted solution were purified by colomun chlomatography (Merck Silica Gel 60 dichloromethane-carbontetrachloride=2:1). m.p. 148-149° C.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][C:8]=1[OH:30])C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][C:8]=1[O:30][CH2:2][C:3]#[N:4]
Reactant: N#CCBr
Reactant: CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCC#N
Temperature: 100 °C
Yield: 35.8 %

Procedure:
Bromoacetonitrile (134 mg, 1.12 mmol), compound 41 (150 mg, 0.449 mmol), and K2CO3 (185 mg, 1.34 mmol) were combined with dry acetone (5 mL) in a sealed microwave vessel. The mixture was heated at 100° C. for 20 min in a Personal Chemistry Emrys Optimizer microwave. The reaction was allowed to cool to room temperature and the solids filtered. The solids were rinsed twice with acetone and the solvent removed in vacuuo. The crude mixture was purified using flash column chromatography with dichloromethane as the eluent to give 60 mg (36%) of 45 as a colorless solid (36%). 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.25 (s, 2H), 1.77 (s, 2H), 1.90 (s, 2H), 2.20 (s, 3H), 4.62-4.68 (s, 2H), 6.78 (d, J=8.1 Hz, 1H) 6.75-7.05 (m, 2H), 7.09-7.25 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Oc1ccc(Cl)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2cc(Cl)ccc2=O)nc1

Procedure:
5-Chloro-2-pyridinol (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25]([Br:27])[CH:24]=[N:23]2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:28]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]([F:28])=[C:25]([Br:27])[CH:24]=[N:23]2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Brc1cnn(C2CCN(Cc3ccccc3)CC2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(Br)cnn1C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of lithium diisopropylamide (1.0 M in THF/hexanes) (1.25 mL, 1.25 mmol) was slowly added to a −78° C. solution of 1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine (200 mg, 0.625 mmol) in THF (2.0 mL), and the reaction was allowed to stir at −78° C. for 1 hour. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (295 mg, 0.937 mmol) was added, and the reaction stirred for an additional 1 hour at −78° C. The reaction was quenched via the addition of saturated aqueous ammonium chloride (5 mL). The reaction was warmed to room temperature and concentrated in vacuo. Ethyl acetate (25 mL) was added, and the organic solution was washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford 1-benzyl-4-(4-bromo-5-fluoro-1H-pyrazol-1-yl)piperidine (53 mg, 25%) as a light yellow oil. MS (ESI, pos. ion) m/z 339 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH2:36]([NH:38][CH2:39][CH2:40][CH3:41])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][N:38]([CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: CCCNCC
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(CC)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 59.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with N-ethyl-1-propylamine (0.242 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (253 mg, 1.19 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(N-ethyl-1-propylaminomethyl)indol-2-yl]isoindolinone (68.4 mg, yield 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:16](=[N:17][CH:18]=1)[C:15]1=[C:19]3C(C[CH2:10][C:11]3=[CH:12][CH:13]=[CH:14]1)=[CH:7]2)([O-:3])=[O:2].[OH2:20].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:33]([OH:36])(=[O:35])[CH3:34]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:16]([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:10](=[O:20])[O:36][C:33](=[O:35])[C:34](=[CH:7]2)[C:19]=34)=[N:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2c(c1)cc1c3c(cccc32)CC1
Reactant: CC(=O)O
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Product: O=C1OC(=O)c2cc3cc([N+](=O)[O-])cnc3c3cccc1c23
Temperature: 0 °C
Yield: 34 %

Procedure:
8-Nitro-10-azaacephenanthrene (3.0 g, 24 mmol) was heated to 70° C. in acetic acid (100 mL) and sodium dichromate dihydrate (18.0 g, 60.4 mmol) was added. The reaction mixture was heated at reflux for 4 h and poured into ice/water. The precipitated solid was collected and dried in vacuo to obtain 1.64 g (34%) of a yellow solid. The crude material was heated at reflux in a mixture of acetic acid (25 mL) and acetic anhydride (5 mL) for 3 h. The mixture was filtered hot and the collected solid was dried in vacuo to give 0.90 g (17%) of a light brown solid: mp 290°-292° C.; MS m/e 312 (M+NH4+); 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (t, J=4.0 Hz, 1H), 8.73 (d, J=7.3 Hz, 1H), 9.33 (s, 1H), 9.54 (d, J=8.0 Hz, 1H), 9.80 (d, J=2.5 Hz, 1H), 9.90 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=O)[C:13]=2[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.CC(C)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2ccc(OCc3ccccc3)c3sc4ccccc4c(=O)c23)cc1
Agent: B
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(OCc3ccccc3)c3c2Cc2ccccc2S3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) suspension of 4-benzyloxy-1-(4-methoxy-benzylamino)-thioxanthen-9-one (8.16 g, 18.00 mmol) in dry THF (150 ml) was added Borane-THF complex (90 mmol, 90 ml 1M in THF) in a dropwise fashion. The reaction was allowed to slowly warm to room temperature and stirred for a further 16 hours to give a homogeneous yellow solution. To mixture was then cooled (0° C.) and diluted slowly with acetone (150 ml) and then stirred for 60 minutes at room temperature. The solvent was removed in vacuo to give a crude residue that was diluted in CH2Cl2 (100 ml) and the washed with a saturated solution of NaHCO3 (100 ml), dried using MgSO4, filtered and concentrated in vacuo to give the title compound as a mild amber oil (7.90 g, 99.8%) m/z (LC-MS, ESP): 438 [M+H]+, R/T=5.01 mins.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[N:15]=[C:14]([S:16]([NH2:19])(=[O:18])=[O:17])[S:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O>>[N:22]1([CH:20]=[N:19][S:16]([C:14]2[S:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:15]=2)(=[O:18])=[O:17])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Reactant: O=CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(N=CN1CCOCC1)c1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (4.5 ml) was added dropwise to 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide in 15 ml of dry N-formylmorpholine at -5°. The resulting mixture was stirred at room temperature for 3 hours, poured into ice water and stirred for 15 minutes. The solids were collected, washed with water, dried, triturated with ether, washed with hexane and dried (in vacuo, P2O5). Recrystallization from benzene/hexane gave 1.1 g of solid, m.p. 185°-187°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])=[C:8]([N+:18]([O-])=O)[CH:7]=1.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O.O.Cl[Sn]Cl>CC(O)=O.CO>[CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]([CH2:13][CH2:14][NH:15][CH2:16][CH3:17])[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:18][C:8]=2[CH:7]=1
Reactant: CCNCCNc1ccc(C=CC(=O)OC)cc1[N+](=O)[O-]
Reactant: CCCCCCC=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCc1nc2cc(C=CC(=O)OC)ccc2n1CCNCC
Temperature: 40 °C

Procedure:
To a stirred solution of 3-[4-(2-ethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (8.174 g, 27.87 mmol) and heptaldehyde (4.85 g, 42.47 mmol, 1.52 eq) in AcOH and MeOH (1:9 v/v, 300 mL) was added SnCl2.2H2O (31.45 g, 139.4 mmol, 5 eq) in portions. The resulting mixture was heated to 40° C. with stirring. The progress of the reaction was monitor by LC/MS. When the reaction was completed, solvent was removed under reduced pressure below 40° C. The resultant residue was diluted with EtOAc (50 mL) then basified (pH>10) with saturated aqueous Na2CO3 and extracted with dichloromethane (×3). Filtration may be needed to remove the white precipitates or suspension derived from Tin in order to get clearly separated layers. The organic extracts were combined, dried (Na2SO4), filtered, and evaporated to dryness. The resulting oily residue was purified by flash column chromatography (silica, φ67×65 mm, solvent MeOH/DCM gradient from 0 to 10%). 3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-acrylic acid methyl ester was obtained as yellow solid (4.445 g, 44.6%). HPLC purity at 254 nm: 98.8%, tR=1.71 min. LCMS (ESI) m/z: 358 ([M+H]+). 1H NMR (CDCl3) δ 7.88 (1H, d, J=1.2 Hz), 7.83 (1H, d, J=16.0 Hz), 7.43 (1H, dd, J=8.4, 1.4 Hz), 7.33 (1H, d, J=8.4 Hz), 6.43 (1H, d, J=15.9 Hz), 4.22 (2H, t, J=6.6 Hz), 3.80 (3H, s), 3.01 (2H, t, J=6.6 Hz), 2.89 (2H, t, J=7.9 Hz), 2.65 (2H, q, J=7.1 Hz), 1.91 (2H, pentet, J=7.8 Hz), 1.46 (2H, m), 1.35 (4H, m), 1.07 (3H, t, J=7.1 Hz), 0.90 (3H, t, J=7.0 Hz). The solid could be recrystallized from Hexanes-ether to give a white or pale yellow solid with HPLC purity at 254 nm: 99.2%.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][CH:33]=2)=[CH:4][N:3]=1.[BH4-].[Na+].CO>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][OH:39])=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(-c2csc3c(-c4ccc(CO)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
N-{4-[4-amino-7-(4-formylphenyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (Example 2, 0.030 g, 0.056 mmol) was dissolved in N,N-dimethylformamide (0.5 mL). Sodium borohydride (0.006 g, 0.167 mmol) and methanol (0.5 mL) were added, and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with aqueous sodium carbonate (1 M, 10 mL) and the product was extracted with methanol dichloromethane (1:33, 3×20 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, using ethyl acetate-heptane (3:1) as the mobile phase, to afford the title compound (0.011 g, 0.020 mmol) as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.00 (d, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.62 (m, 1H), 7.59 (s, 1H), 7.56 (m, 2H), 7.49 (t, 1H), 7.36 (s, 1H), 7.32 (m, 3H), 7.16 (d, 1H), 7.12 (m, 1H), 5.61 (br, 2H), 5.31 (t, 1H), 4.61 (d, 2H), 4.05 (s, 3H), 3.92 (s, 3H); MS: (M−H)− 533.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(OCC)(=O)C.C(OC([N:23]=[C:24]=S)=O)C.O.[NH2:27]O.S([O-])([O-])=O.[Na+].[Na+]>>[NH2:27][C:24]1[N:1]=[C:2]2[N:3]([C:4]([O:10][CH3:11])=[N:5][CH:6]=[C:7]2[O:8][CH3:9])[N:23]=1
Reactant: COc1ncc(OC)c(N)n1
Reactant: NO
Reactant: CCOC(=O)N=C=S
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a 700 milliliter (mL) jacketed vessel equipped with a mechanical stirrer, a dual pH/temperature probe, a nitrogen inlet, and a reflux condenser was added sequentially 19.4 grams (g; 0.125 moles (mol)) of 4-amino-2,5-dimethoxypyrimidine followed by 151 g (1.717 mol) of ethyl acetate. The reaction mixture was heated to reflux (˜80° C.) and then 18.7 g (0.143 mol) of ethoxy carbonylisothiocyanate was continuously added via addition funnel over a 22 minute (min) period. The addition funnel was rinsed with 1.8 g of ethyl acetate and then the reaction mixture was heated at reflux for 9 hours (h). The reaction mixture was cooled to 25° C. and allowed to stand overnight. The mixture was heated to 60° C. and then 100 g (5.500 mol) of deionized water was added to the mixture. After heating to reflux (˜71° C.), 9.4 g (0.142 mol) of a 50 weight percent (wt %) aqueous hydroxylamine solution was continuously added over a 1 h period. During the course of the amine addition, the reaction pH rose from 4.00 to 6.60. The reaction mixture was then heated an additional 3 h during which time the reaction pH naturally lowered to 6.30. To this reaction mixture was added a solution of 4.5 g (0.036 mol) of sodium sulfite in 20 g (1.110 mol) of deionized water over an 8 min period. The reaction pH rose from 6.30 to 7.44 during the sodium sulfite addition. The reaction mixture was then cooled to ambient temperature and allowed to stand overnight. The reaction mixture was suction filtered through a medium coarse fritted glass funnel (filtration time less than 2.0 min), and then the reaction vessel was washed with 150 g of deionized water and this rinse was used to wash the isolated product cake. A final displacement wash with 30 g of fresh deionized water was performed and the product was partially dried by suction for 3.5 h to afford 18.01 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine as a light cream colored wet cake. NMR analysis (using benzyl acetate as an internal standard) indicated a 91.6% purity which corresponds to a 67.5% yield. 1H NMR (DMSO-d6, 400 MHz) δ 3.89 (s, 3H), 4.06 (s, 3H), 6.27 (br s, 2H), 7.47 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.37, 57.03, 123.06, 138.59, 143.72, 148.49, 166.01.