Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:14])[C:6]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([OH:23])[CH2:5]2.C=O.O.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][N:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])[CH2:34][O:23][C:6]1([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:5]2
Reactant: O=C(NN=C1c2ccc(F)cc2CC1(O)c1ccc(F)cc1)Nc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(Br)cc1)N1COC2(c3ccc(F)cc3)Cc3cc(F)ccc3C2=N1
Yield: 447.8 %

Procedure:
A mixture of 0.80 g (0.0017 moles) of the product obtained in Step C, 0.25 g (0.0027 moles) of paraformaldehyde, 50 mg of p-toluene sulfonic acid monohydrate and 45 mL of acetonitrile was refluxed for 30 minutes. The resulting mixture was partitioned between chloroform and saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated to give a yellow solid. The solid was triturated with methanol/water, and dried under vacuum to afford 0.57 g of a yellow solid, m.p. 208°-209° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([OH:13])=[CH:6][C:5]=1[NH2:14])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].O>CN(C)C=O>[CH2:23]([O:13][C:7]1[CH:6]=[C:5]([C:4]([C:1](=[O:3])[CH3:2])=[CH:9][C:8]=1[C:10](=[O:12])[CH3:11])[NH2:14])[CH:22]=[CH2:21]
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(N)c(C(C)=O)cc1C(C)=O

Procedure:
Treatment of the product of step (b) (1.5 g) with K2CO3 (1 equivalent) and allyl bromide (2 equivalents) in dimethylformamide (20 ml) at 70° C. for 21/2 hours followed by dilution with water at 70° C. afforded the sub-title product, as a pale yellow solid (83%) mp 131°-134°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])[CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)C2CCCCC2)CCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-chloro-4-(2-methylpiperazin-1-yl)phthalazine (JK-2, 752 mg, 2.86 mmol) was dissolved in DMF (8 mL) and N,N-diisopropylethylamine (1.5 mL). Cyclohexanecarbonyl chloride (0.498 mL, 3.72 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-75% ethyl acetate gave an off-white foam. MS (M+H)+=373.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:21]=[C:16]([Br:15])[CH:17]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: CC(C)COc1cc(Br)cc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc(Oc2cc(Br)cc(OCC(C)C)c2)cc1C

Procedure:
(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1 mmol), 3-Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol), copper(II) acetate (199 mg; 1.1 mmol), crushed molsieves (about 1 g) and triethylamine (0.46 ml; 3.3 mmol) was dissolved in dichloromethane (40 ml) and stirred over night. The reaction mixture was filtered through celite and evaporated to dryness. The crude product was purified by preparative HPLC (method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5 (M+); Rt: 2.71 min
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][CH:3]=1.[OH-:11].[Na+].[OH2:13]>C(O)(C)(C)C>[C:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:13])=[O:11])=[CH:4][CH:3]=1)#[N:10]
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 5 °C
Yield: 120.1 %

Procedure:
Terephthalonitrile (12.8 g), sodium hydroxide (2.4 g), water (1.5 g), tert-butyl alcohol (300 ml) were mixed, and the resultant mixture stirred vigorously at 80° C. After the solvent was removed through distillation, sodium nitrite (16.6 g), acetic acid (250 ml), and acetic anhydride (25 ml) were added to the residue, and the resultant mixture was stirred vigorously at 5° C. Trifluoroacetic acid (27 g) was added dropwise to the mixture over three hours, and the mixture was further stirred vigorously for five hours. The solvent was removed through distillation under reduced pressure, and water (500 ml) was added to the residue. Sodium hydroxide was added to the solution under cooling with ice so as to adjust the pH to 8. After insoluble matter was removed through filtration, concentrated sulfuric acid was added to the filtrate under cooling with ice so as to adjust the pH to 4. Precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 10.6 g of p-cyanobenzoic acid (yield 72%). The obtained p-cyanobenzoic acid had a purity of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][C@H:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C@@H:18]([C:21]([O:23]CC)=[O:22])[CH2:19][O:20][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:29])[CH2:9][NH:10][C@H:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C@@H:18]([C:21]([OH:23])=[O:22])[CH2:19][O:20][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)ccc2O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1ccc2c(c1)OC[C@H](C(=O)O)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 67.9 %

Procedure:
To a solution of ethyl 6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylate (650 mg) in ethanol (2 ml) were added water (20 ml) and concentrated hydrochloric acid (0.32 ml). This solution was stirred under reflux-heating for 5 hours while removing ethanol with Dean-Stark apparatus. After the solution was concentrated under reduced pressure, acetonitrile/water (1/1) (11 ml) was added to the residue, which was then dissolved under heating. The solution was neutralized with a 5% aqueous solution of sodium hydrogencarbonate. Acetonitrile (20 ml) was added, and the crystals precipitated were dissolved under heating. The resulting solution was filtered under heating and then cooled, and the resulting crystals were filtered to give 6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylic acid (412 mg). The HPLC-2 analysis of the optical isomer showed 96.5% purity (R/S=96.5/3.5, the purity of the material optical isomer used=90.5%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:9])[CH3:8].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:1][N:2]1[CH2:6][CH:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]1([CH3:9])[CH3:8]
Reactant: C1CCNC1
Reactant: CN1CCC(=O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CN1CC=C(N2CCCC2)C1(C)C
Temperature: 25 °C

Procedure:
1,2,2-Trimethylpyrrolidin-3-one (1.00 g) was dissolved in cyclohexane (5 mL). Pyrrolidine (1.31 mL) and p-toluenesulfonic acid monohydrate (7.48 mg) were sequentially added thereto, and the mixture was heated under reflux for 3 days, and allowed to cool to room temperature. The resultant mixture was concentrated under reduced pressure to thereby give a crude product of 1,2,2-trimethyl-3-(pyrrolidine-1-yl)-2,5-dihydro-1H-pyrrole (972 mg). To the product dissolved in dimethylformamide (10 mL), formamidine disulfide hydrochloride (1.20 g) was added, followed by stirring at room temperature for 4 days. The resultant mixture was concentrated under reduced pressure. Methanol (50 mL) and sodium carbonate anhydrate (20 g) were added to the residue, and the resultant mixture was stirred at room temperature for 1 hour. The insoluble material was removed through filtration, followed by washing with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (methanol methylene chloride=1:99→1:9), to thereby give the title compound (580 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH:32](Cl)[CH3:33])[CH3:29]>CN(C=O)C.O>[C:16]1([CH2:15][CH2:14][CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:33][CH2:32][CH:31]([O:35][CH2:36][CH3:37])[O:30][CH2:28][CH3:29])[CH:3]=3)[C:8]2=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(OCC)C(C)Cl
Reactant: O=C1c2ccc(O)cc2CCN1CCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O)OCC

Procedure:
A solution of 6-hydroxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline (7.55 g, 26.87 mmol), Cs2CO3 (18 g, 53.74 mmol) and chloropropionaldehyde diethyl acetal (5.4 mL, 32.2 mmol) in DMF (100 mL) is stirred for 48 hours. After this time the reaction is diluted with H2O (400 mL) and the resulting mixture extracted with EtOAc (2×200 mL). The combined organic phases are washed with saturated NaCl solution (2×400 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:9 EtOAc/hexane ) to give 2-(3-phenylpropyl)-6-(3,3-diethoxypropyloxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline which is hydrolyzed with 6N HCl in tetrahydrofuran at room temperature to yield β-[2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-propionaldehyde.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O>CN(C)C=O>[F:22][C:21]([F:24])([F:23])[CH2:20][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11]
Reactant: O=Cc1cc2cccnc2[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc2cccnc2n1CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.8 g, 12.32 mmol) was added to a solution of sodium hydride (0.54 g, 13.55 mmol) in N,N-dimethylformamide (50 mL) at rt under nitrogen. The reaction mixture was allowed to stir for 1 h before the reaction mixture was cooled to 0° C. and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.04 ml, 14.78 mmol available, for example, from Sigma Aldrich) was added dropwise. The reaction mixture was stirred for 1 h at 0° C. and for 14 h at rt under nitrogen. The reaction was quenched by addition of water (150 mL). After addition of Et2O (150 mL), the layers were separated. The aqueous layer was further extracted with Et2O (3×150 mL) and the combined organic layers were washed with H2O. The combined water layers were extracted with Et2O (150 mL). The organic layers collected were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was loaded in dichloromethane on two 100 g SNAP silica cartridge and purified by SP4, eluting with 0-30% ethyl acetate/cyclohexane gradient. The appropriate fractions were combined and evaporated under reduced pressure to give the required product 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.6 g, 11.39 mmol, 93% yield) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].NC1C=CC([C:28]2[NH:29][C:30]3[CH:36]=[CH:35][C:34](N)=[CH:33][C:31]=3[N:32]=2)=CC=1>CN(C=O)C.N1C=CC=CC=1>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([C:28]2[NH:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)=[O:20])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](C(=O)c2nc3ccccc3[nH]2)CC1

Procedure:
Bis-trans-4-pentylcyclohexyl carbonyl benzimidazole was synthesized as follows: oxalyl chloride (1.07 ml, 2 M in CH2Cl2) was added to trans-4-pentylcyclohexyl carboxylic acid (0.424 g, 2.14 mmole) followed by one drop DMF. The mixture was allowed react at RT for 1 hour. To the above solution was added 2-(4-aminophenyl)-6-amino-benzimidazole (0.200 g, 0.89 mmole) in pyridine (2 ml). The
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[CH:35]1([C:38]2[CH:39]=[C:40]([NH2:48])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[CH2:37][CH2:36]1>C1COCC1>[CH:35]1([C:38]2[CH:39]=[C:40]([NH:48][C:15]([C@@:11]3([CH:18]([CH3:19])[CH3:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10]3)=[O:16])[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=2)[CH2:36][CH2:37]1
Reactant: Nc1cc(C2CC2)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C3CC3)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (32 mg, 0.12 mmol) and methanesulfonyl chloride (12 μL, 0.15 mmol) in THF (0.6 mL) at 0° C. was added diisopropylethylamine (0.060 mL, 0.35 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-cyclopropyl-5-(trifluoromethyl)benzenamine (47 mg, 0.23 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 9.89 (s, 1H), 7.86 (s, 1H), 7.56 (s, 1H), 7.05-7.17 (m, 4H), 3.97 (d, J=10.4 Hz, 1H), 3.67 (d, J=10.4 Hz, 1H), 3.04 (d, J=17.2 Hz, 1H), 2.65 (d, J=17.2 Hz, 1H), 2.36 (septet, J=6.8 Hz, 1H), 2.16 (s, 3H), 1.99-2.08 (m, 1H), 1.99 (s, 3H), 1.00-1.06 (m, 2H), 0.96 (t, J=6.8 Hz, 6H), 0.70-0.75 (m, 2H). LC-MS Rt (retention time): 3.02 min; MS: (ES) m/z 459 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C.C1COCC1>[CH2:33]([O:18][C@H:13]1[C@H:14]([O:17][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:15]([O:16][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:10]([C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)[CH:4]=2)[O:11][C@@H:12]1[CH2:19][O:20][CH2:10][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 182.2 %

Procedure:
To a solution of compound 75 (4.12 mmol) in DMF/THF (20 mL/60 mL) at 0° C. under an atmosphere of nitrogen were added NaH (60% oil, 825 mg, 20.6 mmol) and benzyl bromide (4.9 mL, 41.2 mmol) dropwise, and the mixture was stirred for 16 hours at the room temperature. To the mixture was added water (20 mL) to quench the reaction. After dilution with water, the mixture was stirred at room temperature for 30 min and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 76 (3.0 g, 93%) as colorless oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][CH2:33][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:29]([OH:34])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]([CH2:15][CH3:16])(O)[C:11](O)=[O:12])[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>CCCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][CH3:16])[C:11](=[O:12])[NH:18][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CC(=O)c1cccc(Cl)c1)C(=O)O
Reactant: NN
Solvent: CCCCO
Product: CCc1cc(-c2cccc(Cl)c2)n[nH]c1=O
Temperature: 130 °C

Procedure:
A RBF was charged with 4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid (2.78 g, 10.8 mmol), hydrazine (0.510 ml, 16.2 mmol) and 11 mL of n-BuOH. A Dean-Stark apparatus fitted with a reflux condenser was attached, and the mixture was heated under nitrogen at 130° C. for 15 h. Upon cooling a precipitate formed, which was filtered, washed with cold EtOH, and dried. 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one was isolated as a white solid. MS m/z=235 [M+H]+. Calc'd for C12H11ClN2O: 234.68.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]2[CH2:16][O:15]C(C)(C)[O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(O)C.Cl>O1CCCC1>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]([OH:13])[CH2:16][OH:15])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(C)OC[C@@H](CCn2cc([N+](=O)[O-])nc2Cl)O1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(CC[C@@H](O)CO)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
While stirring a tetrahydrofuran solution (700 ml) of 2-chloro-1-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)ethyl]-4-nitro-1H-imidazole (196.2 g) at room temperature, 1.0 M hydrochloric acid ethanol solution (1,100 ml) was added thereto and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue obtained and concentrated under reduced pressure. Thereafter, ethyl acetate was added thereto and concentrated under reduced pressure. Isopropyl ether was added to the resulting solid and stirred for a while. The precipitated crystal was collected by filtration to afford the title compound as a colorless solid (166.5 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:12][CH2:13][CH3:14])([CH2:6][NH:7][C:8](=S)[S:9]C)=[O:5])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C.O>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:8]([SH:9])=[N:17][N:16]=[N:15]1)([O:12][CH2:13][CH3:14])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CNC(=S)SC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(Cn1nnnc1S)OCC

Procedure:
To a solution of 2.85 g (11.1 mmol) of methyl 1-diethoxyphosphinylmethyldithiocarbamate in 25 ml of ethanol was added a solution of 0.72 g (11.1 mmol) of sodium azide in 5 ml of water. The reaction mixture was refluxed for 2.5 hours then evaporated to near dryness. Water (20 ml) was added and the aqueous mixture was layered with 40 ml of ethyl acetate and acidified to pH 2.2 by addition of 6N sulfuric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The ethyl acetate solutions were combined, dried (MgSO4) and evaporated to dryness to give 1-diethoxyphosphinylmethyltetrazole-5-thiol.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([CH3:13])=[CH:12][C:7]=1[CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c(Br)c(=O)n1Cc1cccnc1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a degassed solution of 3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl2(PPh3)2 (0.11 g) were added. The reaction mixture stirred at room temperature under nitrogen for 1 hour and then heated in an oil bath (65° C.) under nitrogen overnight. The solvents were distilled in vacuo and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). The extracts were concentrated to afford the desired compound (0.432 g, 69%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J=8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z 397.0361/399.0310 (M+H calculated for C20H15N2OFBr requires 397.0346/399.0328). Step 3. Preparation of 3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)(=O)(=O)C.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 3-(4-pentylphenyl)propyl mesylate (42.4 g, 149 mmol) and potassium phthalimide (27.6 g, 149 mmol) in DMF (200 ml) was stirred at 80° C. for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the object compound as an oily substance. 41.1 g, (yield 82%)