Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:13]([O:15][CH2:30][CH3:31])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2
Reactant: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid (5G) (180 mg, 0.49 mmol) in DMF (15 mL) was added cesium carbonate (321 mg, 0.98 mmol) at 0° C. After being stirred for 10 min iodoethane (0.059 mL, 0.74 mmol) was added. The mixture was stirred at room temperature for 2 hours and quenched by the slow addition of a NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the pure product 5H (168 mg, 87%). LCMS-ESI+ (m/z): 394.1, 396.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)O)=[CH:7][C:6]=2[CH:19]=1.S(Cl)([Cl:22])=O>C(Cl)Cl.C1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:22])[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:19]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc2cc(Br)ccc2o1
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h

Procedure:
To 36.2 g of (5-bromobenzofuran-2-yl)(p-chlorophenyl)methanol dissolved in 50 ml of methylenchloride, 8.5 ml of thionylchloride in 25 ml of cyclohexane are added drop by drop, under agitation. After a 4 hour rest at 10° C., the solution is brought to dryness under vacuum condition. The residue is crystallized from petroleum ether: m.p. 83°-85° C.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:19]([CH2:18][N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A 125-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 115h (5.76 g, 29.8 mmol) and DMF (50 mL). The solution was cooled to 0° C. using an ice bath. NaH (60% dispersion in mineral oil, 1.43 g, 35.8 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. After that time, bromoacetonitrile (1.43 g, 35.8 mmol) was added. The mixture was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and water (450 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 55% yield (3.80 g) of 115i as a yellow semi-solid: 1H NMR (300 MHz, CDCl3) δ 6.66 (s, 1H), 5.29 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 2.62 (t, 2H, J=6.3 Hz), 2.49 (t, 2H, J=6.3 Hz), 1.92 (m, 2H), 1.75 (m, 2H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 233.1 (M+H)
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[OH-].[CH2:13]([N+:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].CO>O>[CH2:26]([N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH3:29].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([O-:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer, pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and tetrabutylammonium hydroxide, 1.0 M in methanol (1.2 l, 1.2 mol). The reaction mixture was stirred at 0˜5° C. for 2 hours to afford (S)-3,4-epoxybutyric acid tetrabutyl ammonium salt. Over 99% of conversion was detected by NMR.
Reaction SMILES: CO.[Na].[SH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl[C:12]1[C:13]([C:22]#[N:23])=[N:14][C:15]([C:20]#[N:21])=[C:16](Cl)[C:17]=1Cl>CC(C)=O>[N:8]1[CH:9]=[CH:10][C:5]([S:4][C:12]2[C:13]([C:22]#[N:23])=[N:14][C:15]([C:20]#[N:21])=[C:16]([S:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)[C:17]=2[S:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccncc1
Reactant: N#Cc1nc(C#N)c(Cl)c(Cl)c1Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CO
Product: N#Cc1nc(C#N)c(Sc2ccncc2)c(Sc2ccncc2)c1Sc1ccncc1
Reaction time: 0.08 h
Yield: 45.7 %

Procedure:
In a 500 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a calcium chloride drying tube were placed 250 ml of methanol and 2.30 g (0.10 mol) of sodium metal. After all of the sodium had reacted, 11.11 g (0.10 mol) of 4-mercaptopyridine was added and the solution was allowed to stir for five minutes. To the resulting thiolate solution, 7.65 g (0.033 mol) of 3,4,5-trichloro-2,6-pyridinedicarbonitrile was added. The reaction mixture immediately became cloudy and orange in color. The reaction mixture was heated to reflux and then cooled. The methanol was removed in vacuo leaving a red-orange gum. Mixing of the gum with acetone, filtering off the solid and drying the latter afforded 6.89 g of the title compound as a yellow to orange powder, m.p. 186°-189° C (dec.). A 1.00 g sample was recrystallized from absolute ethanol to give a 0.25 g analytical sample as small, yellow-orange crystals, m.p. 186°-189° C (dec.). Anal. % Calcd. for C22H12N6S3 : C, 57.87; H, 2.65; N, 18.41. Found: C, 57.64; H, 2.59; N, 18.22.
Reaction SMILES: BrCC(=[O:11])CCC=C(C)CC.[Br:12][CH2:13][C:14](=[O:23])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:22])[CH2:19][CH2:20][CH3:21].[Br:24][CH2:25][C:26](=[O:37])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[Br:24][CH2:25][C:26](=[O:37])[CH2:27][CH2:28][CH:29]1[O:11][C:30]1([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[Br:12][CH2:13][C:14](=[O:23])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(C)=CCCC(=O)CBr
Reactant: CCC(C)=CCCC(=O)CBr
Reactant: CCCC(C)=CCCC(=O)CBr
Product: CCCC(C)CCCC(=O)CBr
Product: CCCCCC1(C)OC1CCC(=O)CBr

Procedure:
When in the above procedure 1-bromo-6-methyl-2-oxo-oct-5-ene and 1-bromo-6-methyl-2-oxo-non-5-ene are employed in place of 1-bromo-6-methyl-2-oxo-undec-5-ene, the corresponding 1-bromo-5,6-epoxy-6-methyl-octan-2-one and 1-bromo-6-methyl-nonan-2-one are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH2:8][NH:7][C:6]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:13][C:5]=2[CH2:4][NH:3]1.FC(F)(F)C(O)=O.C(Cl)[Cl:31]>CCOCC>[ClH:31].[O:1]=[C:2]1[CH2:9][CH2:8][NH:7][C:6]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:13][C:5]=2[CH2:4][NH:3]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CNC(=O)CCN2
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CNC(=O)CCN2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of (E)-tert-butyl 3-(4-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocin-8-yl)acrylate (175 mg, 0.58 mmol) in 3 mL CH2Cl2 was treated with 3 mL of trifluoroacetic acid. The mixture became homogeneous and it was stirred at room temperature for 20 minutes. The solution was concentrated to dryness and treated with 1 mL 4M HCl in dioxane to give a creamish solid. The suspension was diluted with 10 mL Et2O and sonicated. The solid was filtered and dried under reduced pressure overnight. Yield: 165 mg (100%) 1H-NMR (400 MHz, DMSO-d6) δ 8.28-8.27 (2×s, 2H), 8.26 (br s, 1H), 7.60 (t, 1H, J=7.6 Hz), 7.51 (d, 1H, J=16.0 Hz), 6.50 (d, 1H, J=16.0 Hz), 4.62 (br s, 2H), 3.85 (br s, 2H), 2.79 (t, 2H, J=7.2 Hz)
Reaction SMILES: [N:1]([CH:4]([CH3:20])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([CH2:16][CH:15]=1)=[C:9]1[C:10]([N:6]([CH2:5][CH:4]([NH2:1])[CH3:20])[N:7]=[CH:8]1)=[CH:11]2
Reactant: COC1=CCC2=c3cnn(CC(C)N=[N+]=[N-])c3=CC2=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: COC1=CCC2=c3cnn(CC(C)N)c3=CC2=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
1.58 g (5.86 mmol) of (RS)-1-(2-azido-propyl)-6-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 160 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 680 mg (5.86 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.81 g (86%) of (RS)-2-(6-methoxy-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 192°-194° were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(Cl)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cc(Cl)cc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14 %

Procedure:
To a solution of ethyl 7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (429 mg, 1.05 mmol) in methanol (15 mL) was added hydrazine monohydrate (2 mL). The mixture was stirred at 25° C. for 5 hr. The resulting mixture was concentrated under reduced pressure to a volume of 10 ml and then filtered, giving 58 mg of solid (yield 14%). LC-MS (ESI) m/z: 378 (M+1)+; 379 (M+2)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 (s, 3H), 4.69 (d, J=10.0 Hz, 1H), 4.98 (d, J=10.4 Hz, 1H), 5.76 (s, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.14 (s, 1H), 7.27 (dd, 4H), 7.38 (d, J=6.4 Hz, 2H), 7.62 (s, 1H), 12.36 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](OCC)=[O:24].CCCCCC>O1CCCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](=[O:24])[CH2:17][C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccco1
Reaction time: 2 h
Yield: 70.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (100 mL, 100 mmol) was added dropwise over 1 hour to a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 mL) at 0° C. in a nitrogen atmosphere, followed by stirring as such for 2 hours. Hexane (140 mL) was added to the reaction solution, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution (×2) and brine, dried over anhydrous sodium sulfate, and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[C:7]([C:9](Cl)=O)[CH:6]=[CH:5][N:4]=1.[O:12]1[CH2:16]CCC1>>[Cl:2][C:3]1[N:8]=[C:7]([CH2:9][C:16]([NH2:1])=[O:12])[CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1ccnc(Cl)n1
Reactant: C1CCOC1
Reactant: N
Product: NC(=O)Cc1ccnc(Cl)n1
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Ammonia gas was introduced in 20 ml of tetrahydrofuran at -6° C. for 35 minutes. Then it was heated to 10° C. and 1.5 g (8.47 mmol) of 2-chloropyrimidine-4-carboxylic acid chloride was added. The reaction solution was stirred for 45 minutes at room temperature. Then it was concentrated by evaporation on a rotary evaporator, the residue was poured on 90 ml of saturated NaHCO3 solution, and the aqueous phase was extracted three times with 50 ml of ethyl acetate each. The combined organic phase was washed with saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation on a ratory evaporator. After drying on a high vacuum, 1.07 g of product was obtained as a white solid, corresponding to a yield of 80 percent relative to the 2-chloropyrimidine-4-carboxylic acid chloride used. The melting point of the product was 147.2° to 151.4° C. Other data of the product was:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](OC(C)(C)C)=[O:52])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])C(O)=O)=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:8])[CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:34]4[CH:35]=[C:58]5[C:59]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](=[O:52])[C@@H:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[CH:69]([CH3:71])[CH3:70])[NH:40][C:39]=65)=[CH:32][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1
Yield: 71.3 %

Procedure:
tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (32 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (80 mg, 71%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=[O:46]>>[OH2:24].[OH2:46].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCN(CC)CC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCN(CC)CC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: O

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-methyl-7-(2-diethylamino-ethoxy)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:1]1[CH2:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: c1coc(CCc2ccncc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C1=C(CCc2ccco2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 1-(pyridin-4-yl)-2-(furan-2-yl)ethane (2 g, 11.6 mmol) in anhydrous dimethylformamide (5 ml) was treated with benzyl bromide (1.5 ml, 12.7 mmol) and the reaction stirred at room temperature for one hour. The reaction was diluted with ethanol (50 ml), treated with sodium borohydride (0.55 g, 14.5 mmol) and heated at reflux for one hour. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic was separated, dried (Na2SO4) and evaporated to give crude product as a yellow oil. This material was triturated with diethyl ether to afford the title compound (2.3 g, 68%) as a colourless solid; δH (DMSO-d6) 1.92-2.10 (2H, m, tetrahydropyridinyl CH2), 2.14-2.30 (2H, m, CH2), 2.36-2.50 (2H, m, CH2), 2.60-2.82 (2H, m, tetrahydropyridinyl CH2), 2.84-2.90 (2H, m, tetrahydropyridinyl CH2), 3.50 (2H, br s, PhCH2N), 5.32-5.44 (1H, m, tetrahydropyridinyl 5-H), 6.02-6.10 (1H, m, furanyl H), 6.30-6.36 (1H, m, furanyl H), 7.16-7.36 (5H, m, ArH), and 7.44-7.52 (1H, m, furanyl H); m/z (CI+, NH3) 268 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[N:34]1[N:38]2[CH2:39][CH2:40][NH:41][CH2:42][C:37]2=[CH:36][C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:41]2[CH2:40][CH2:39][N:38]3[N:34]=[C:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:36]=[C:37]3[CH2:42]2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cc2n(n1)CCN(C(=O)c1ccc(OC)cc1)C2
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of 4-methoxybenzoic acid (0.187 g, 1.23 mmol) dissolved in N,N-dimethylformamide (5 mL) and triethylamine (0.428 mL, 3.07 mmol) was added tetramethylfluoroformamidinium hexafluorophosphate (0.406 g, 1.54 mmol) and the reaction mixture was stirred for 15 minutes. Ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.2 g, 1.02 mmol) was added and the reaction continued to stir at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via silica gel chromatography (0-90% EtOAc/hexane) to afford ethyl 5-(4-methoxybenzoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Intermediate 27 (0.359 g, 100%). LC-MS: (FA) ES+330.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5](=[CH:8][C:9]=1[OH:10])[C:6]#[N:7].[CH2:13]([O:15][CH:16]([O:23][CH2:24][CH3:25])[CH2:17][CH:18]([CH2:21]O)[CH2:19]O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:24]([O:23][CH:16]([O:15][CH2:13][CH3:14])[CH2:17][CH:18]1[CH2:19][O:10][C:9]2[CH:8]=[C:5]([C:6]#[N:7])[C:4]([C:11]#[N:12])=[CH:3][C:2]=2[O:1][CH2:21]1)[CH3:25]
Reactant: CCOC(CC(CO)CO)OCC
Reactant: N#Cc1cc(O)c(O)cc1C#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(CC1COc2cc(C#N)c(C#N)cc2OC1)OCC
Temperature: 75 °C

Procedure:
To the mixture of 4,5-dihydroxy-phthalonitrile (2.50 g, 15.6 mmol), 2-(2,2-diethoxy-ethyl)-propane-1,3-diol (4.5 g, 23.4 mmol) and triphenylphosphine (6.138 g, 23.4 mmol) in THF (40 mL) was added diethyl azodicarboxylate (4.08 g, 23.4 mmol) and the resulting mixture heated at 75° C. overnight. The resulting mixture was then cooled to room temperature and evaporated in vacuo to yield a solid, which was purified via flash column chromatography (EA/Hex 2:3) to yield 3-(2,2-diethoxyethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7,8-dicarbonitrile as a white solid. MS MH+=317, 1H NMR (CDCl3) δ 7.29 (s, 2H), 4.58 (m, 1H), 4.46 (m, 2H), 4.19 (m, 2H), 3.66 (m, 2H), 3.52 (m, 2H), 2.60 (m, 1H), 1.78 (m, 2H), 1.20 (t, J=7.0 Hz, 6H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:11]=2[CH:10]=[CH:9][N:8]=1.[OH-].[Na+]>Cl>[NH2:6][C:7]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(CNc2nccc3c2C(=O)N(C)C3)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1Cc2ccnc(N)c2C1=O

Procedure:
A solution of 4-[(2,4-dimethoxybenzyl)amino]-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (1.8 g, 5.7 mmol) in 37% HCl (7.0 mL) was stirred at rt for 16 hours. The reaction mixture was neutralized with NaOH and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a red solid. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an orange solid, (319 mg, 34%). 1H NMR (DMSO-d6, 400 MHz): δ=2.99 (s, 3 H), 4.37 (s, 2 H), 6.54 (br. s., 2 H), 6.73 (d, J=5.05 Hz, 1 H), 8.04 (d, J=5.05 Hz, 1 H). MS (ES+): m/z 164.07 [MH+] (TOF, polar).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:40](=[O:39])[CH2:41][OH:42])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.