Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:18])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (5.7 g, 30 mmol) in dichloromethane (100 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added slowly oxalyl chloride (5.08 mL, 60 mmol). After stirring for 2 hours, the mixture was concentrated and the residue was used without further purification.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][CH2:14][C:15]([NH:17][CH:18]1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:16].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>ClCCl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[NH:20]1[CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:30])[F:29])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1

Procedure:
A solution of tert-butyl 3-(2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step F) (1 g, 2.35 mmol, 1.00 equiv) in dichloromethane (10 mL) and TFA (25% in DCM, 1 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum, and the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1([CH3:23])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:56]>CO>[ClH:56].[S:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][C:2]3([CH3:23])[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:6][CH2:7]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CC1(N)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cc2c(cn1)OCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(NCc2cc3c(cn2)OCCS3)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Product: Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
A suspension of (1R)-1-[(4-amino-4-methyl-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (34 mg, 0.108 mmol) in chloroform (2 ml) and methanol (0.1 ml) at rt under argon was treated with 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (19.60 mg, 0.108 mmol) (for a synthesis see WO2004058144, Example 60) and stirred for 2 h. The solution was then treated with sodium triacetoxyborohydride (68.8 mg, 0.324 mmol) and stirred at rt for 0.5 h. The reaction was then treated with saturated aqueous NaHCO3 (20 ml) and extracted with 20% methanol/DCM (3×100 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM, Rf=0.4 in 15% methanol/DCM) to give the free base of the title compound as a light brown solid (32 mg, 0.067 mmol, 62%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[C:37]([CH3:42])=[N:38][O:39][C:40]=1[CH3:41].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[C:37]([CH3:42])=[N:38][O:39][C:40]=2[CH3:41])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1noc(C)c1CCl
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2c(C)noc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), potassium carbonate (1.28 g), 4-(chloromethyl)-3,5-dimethylisoxazole (0.45 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.43 g, 33%).
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22](C5CCCCC5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[N+:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1C(=O)C)([O-])=[O:38].[OH-:49].[K+]>C(O)C>[N+:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:13]1([C:18]2[NH:22][C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=2)[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][CH:17]=[CH:16][C:15]=2[CH2:14]1)([O-:38])=[O:49]
Reactant: [OH-]
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(C3(c4ccccc4[N+](=O)[O-])C=Cc4ncccc4C3)nc2c1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2-nitro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (11 mg, 10% yield). MS: 493.21 (M+H+); HPLC Procedure A, retention time=12.72 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:3].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:24]CCOC)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O1[CH2:34][CH2:33][O:32][CH2:31]C1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1.[CH3:31][O:32][CH2:33][CH2:34][N+:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C1COCCO1
Reactant: CCCCCCCCCCN(C)C
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Product: CCCCCCCCCC[N+](C)(C)CCOC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 75 °C

Procedure:
The reaction was performed in an inert atmosphere. N,N-dimethyldecylamine (16.21 mmol, 3.7 g) and 2-methoxyethyl 4-methylbenzenesulfonate (16.21 mmol, 3.71 g) prepared in the previous step were mixed together in a round bottom flask. Dioxane (10 mL) was added to the reaction mixture. The reaction mixture was heated at 75° C. for 18 hours. The solvent was removed by a rotoevaporator, and the remaining viscous liquid was cooled and dried. A white solid was obtained as N-(2-methoxyethyl)-N,N-dimethyldecan-1-aminium 4-methylbenzenesulfonate. The reaction was also performed in absence of any solvent and the desired product was obtained in quantitative yield. Similarly other surfactants were synthesized following the above-mentioned method.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][O:22][C:21]3=[O:30])[CH2:16][CH2:15]2)=[C:10]([Cl:31])[CH:9]=1.C(N(CC)CC)C>ClCCl>[Cl:31][C:10]1[CH:9]=[C:8]([NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:13]=[CH:12][C:11]=1[N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][O:22][C:21]2=[O:30])[CH2:18][CH2:19]1
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
Isobutyryl chloride (0.017 ml) was added to a stirred solution of the product from example 120 step (ii) (0.05 g) and triethylamine (0.07 ml) in dichloromethane (1 ml) at room temperature. After 2 h the mixture was partitioned between ethyl acetate and water, the organics separated, washed with water, dried, and evaporated under reduced pressure. Trituration with ether gave a solid, yield 0.048 g.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.CCN(CC)CC>CN(C=O)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][C:17]([OH:20])([CH3:21])[CH2:18][CH2:19]2)[CH3:3])[N:24]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-methylpiperidin-4-ol (56 mg, 0.194 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (32.9 mg, 0.194 mmol) and Et3N (0.054 mL, 0.388 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 5-30% ACN in water (with 0.05% ammonium carbonate). The fractions containing the desired product were combined and lyophilized to give the title compound (racemate) as a white solid (40 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.29 (m, 3 H), 1.32-1.43 (m, 3 H), 1.52-1.87 (m, 4 H), 2.57-2.72 (m, 2 H), 2.73-2.94 (m, 2 H), 3.16-3.29 (m, 1 H), 3.71-3.86 (m, 3 H), 4.24-4.32 (m, 1 H), 5.74-5.88 (m, 1 H), 6.34-6.44 (m, 2 H), 6.44-6.52 (m, 1 H), 6.53-6.65 (m, 3 H), 7.48-7.58 (m, 1 H), 7.77-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H27N9O, 422.2; found 422.5.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[ClH:33].C(OCC)(=O)C>C(OCC)C>[ClH:33].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), dimethylcarbamoyl chloride (72.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent is was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow powder (42.8 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH3:10])[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[CH2:17]([O:16][C:14]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH3:10])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C[C@H](N)C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of the 5,5,5-trifluoro-L-leucine (12 g) in H2O (150 mL) at 0° C. was added benzyl chloroformate (4.8 mL, 34 mol), followed by dropwise addition of 1 M aqueous NaOH (120 mL, 120 mmol). More benzyl chloroformate (4.8 mL, 34 mmol) was added. The mixture was further stirred at 0° C. and the pH of the mixture became ˜7. The mixture was washed with Et2O (2×) and acidified with aqueous HCl. The aqueous layer was extracted with EtOAc (3×), dried (Na2SO4) and concentrated in vacuo to provide N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucine. The crude acid was dissolved in Et2O and treated with a solution of diazomethane in Et2O. Chromatography over silica gel and elution with hexanes:Et2O (7:3) gave methyl (4S)—N—[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucinate as the less polar fraction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]/[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:10]/O)[CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10]2)[CH:3]=1
Reactant: COc1ccc(/C(Cc2cc(Br)ccn2)=N\O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (Z)-2-(4-bromopyridin-2-yl)-1-(4-methoxyphenyl)ethanone oxime (2.7 g, 8.4 mmol) and triethylamine (4.7 mL, 33.6 mmol) in dichloromethane at 0° C., was added trifluoroacetic anhydride (1.3 mL, 9.2 mmol). The mixture was stirred at 0° C. for 20 minutes then at room temperature for 5 hours. A saturated solution of ammonium chloride (20 mL) was added and the mixture was diluted with dichloromethane (20 mL). The separated aqueous layer was extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a residue which was purified by automated flash-chromatography (ethyl acetate/hexanes; 5/95). The title compound was obtained as a colorless solid (2.1 g, 83%); LCMS m/z 303.0, 305.0 (M+H)+, ret. time 2.57 min.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([O:32][CH3:37])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:33][CH:34]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)C(CC(O)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(CC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1)c1ccccc1
Yield: 84.1 %

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine (0.051 g, 0.11 mmol) in anhydrous ether (5 mL) was added sodium hydride (0.006 g, 0.15 mmol). The resultant mixture was stirred at ambient temperature for 30 minutes, then methyl iodide (0.016 g, 0.11 mmol) was added. Once thin layer chromatography analysis showed complete consumption of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine had occurred, the mixture was poured into water and extracted with two portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford 0.046 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-methoxy-2-phenylethyl)piperazine as a yellow oil: NMR (CDCl3) 7.3 (m, 9), 7.0 (m, 2), 6.9 (m, 2), 4.8 (m, 3), 4.2 (m, 2), 3.9-32 (m, 5), 3.1 (d, 2), 3.0 (s, 1), 2.9 (s, 1), 2.6 (m, 1), 2.4 (m, 1), 1.9 (m, 1) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]([F:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:32]OS(C(F)(F)F)(=O)=O>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:32][C:31]([F:47])([F:30])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCCCCC1
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3ccccc3)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
To a mixture of 1-(3-hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester (80 mg, 0.249 mmol) and potassium carbonate (83 mg, 0.60 mmol) in 0.5 ml of acetone and 0.5 ml of DMF was added slowly a solution of the compound of step 1 (0.22 g, 0.374 mmol) as solution in acetone. The mixture was stirred for 3 d at room temperature and then evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to give the title compound (87 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][CH:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C([O-])(=O)C.[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][CH:19]([O:21][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)Cn1ncc2ccc(OCc3ccccc3)cc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
To a mixture of 1-(6-benzyloxyindazol-1-yl)-propan-2-ol (10 g, 35.5 mmol) in THF (100 mL) and imidazole (3.4 g, 50 mmol) was added tert-butyl-chloro-dimethyl-silane (6.42 g, 42.6 mmol) and the mixture was stirred for 15 min at ambient temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium acetate (300 mL) and extracted with ethyl acetate (2×150 mL). Purification by chromatography (silica, EtOAc/hexane) gave a yellow solid (10.6 g, 76%): mp 56-58° C.; LC/MS (+APCI) m/z 397 (M+H).
Reaction SMILES: S(F)(=O)(=O)[OH:2].[Sb](F)(F)(F)(F)F.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][CH2:23][C:24]#N)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:16]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:2])([O-:14])=[O:13]
Reactant: N#CCCCc1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)F
Agent: F[Sb](F)(F)(F)F
Product: O=C1CCCc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.00 g of fluorosulfuric acid (10 mmol) are added to 1.30 g of antimony(V) fluoride (6 mmol) in a 50 ml glass round-bottomed flask under protective gas and the mixture is cooled to 0° C. Then, 380 mg of 4-(2-nitrophenyl)butyronitrile (2 mmol) are added carefully. The mixture heats up to about 50° C. and is stirred for a farther 12 h at room temperature. The mixture is poured on to ice-cold sodium hydroxide solution, stirring is continued for 30 min at room temperature and then extraction is performed with toluene. Largely complete hydrolysis is made possible by the secondary stirring period. The organic phase is dried over sodium sulfate, filtered off and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (eluent cyclohexane/ethyl acetate 5:1 v/v). The yield of 5-nitro-3,4-dihydro-1(2H)-naphthalenone is 297 mg with a GC purity of 97% (76% of theoretical value).
Reaction SMILES: [C:1](=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH3:9][O:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]([C:23](OCC)=[O:24])[C:20](=O)[CH3:21])[CH:13]=1>CCO>[CH2:9]([O:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]2[C:23]([OH:24])=[N:7][C:6]([NH2:8])=[N:5][C:20]=2[CH3:21])[CH:13]=1)[CH3:1]
Reactant: CCOC(=O)C(Cc1cccc(C(=O)OC)c1)C(C)=O
Reactant: N=C(N)N
Reactant: O=C(O)O
Solvent: CCO
Product: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2O)c1
Yield: 96.9 %

Procedure:
Guanidine carbonate (2.71 g) was added to a stirred solution of 3-(2-ethoxycarbonyl-3-oxo-butyl)-benzoic acid methyl ester (2.12 g) in EtOH (40 mL). The reaction mixture was heated to reflux for 6 h and allowed to cool. The solvent was evaporated under reduced pressure and the residue suspended in water (30 mL). The resulting precipitate was collected by filtration and the solid suspended in EtOAc (30 mL). The solid was collected by filtration to give the subtitle compound as a colourless solid 2.12 g that was used without further purification.
Reaction SMILES: C=C1OC(=O)C1.BrBr.[CH:9]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:23][CH2:24][C:25](=[O:30])[CH2:26][C:27](Br)=[O:28]>C(Cl)Cl.C(N(CC)CC)C>[Br:23][CH2:24][C:25](=[O:30])[CH2:26][C:27]([O:22][CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:28]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CC(=O)CBr
Agent: BrBr
Agent: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In 10.5 ml of methylene chloride there were dissolved 2.1 g of diketene, and at a temperature not exceeding -30° C., a solution of 4.0 g of bromine in 12.5 ml of methylene chloride was added dropwise to the solution with stirring. After the dropwise addition was completed, the mixture was maintained at 0° C. for 10 minutes. Separately, 3.68 g of benzhydrol were dissolved in 25 ml oof methylene chloride, followed by addition of 2.02 g of triethylamine. Under stirring at a temperature not exceeding -30° C., the solution of bromoacetoacetyl bromide prepared above was added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 40 minutes, at the end of which time it was washed with water. After drying over magnesium sulfate the solvent was distilled off under reduced pressure, whereupon 6.99 g of benzhydryl 4-bromo-3-oxobutyrate were obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[N:16]([CH3:17])[CH:15]=[CH:14][C:9]2=[N:10][C:11]=1[C:12]#[N:13].[BH4-].[Na+]>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]2[N:16]([CH3:17])[CH:15]=[CH:14][C:9]2=[N:10][C:11]=1[CH:12]([NH2:13])[CH2:1][CH3:2]
Reactant: Cn1ccc2nc(C#N)c(Br)cc21
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(N)c1nc2ccn(C)c2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Ethylmagnesium bromide (4.18 mL, 12.54 mmol) was added to a stirred solution of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (740 mg, 3.13 mmol) in THF (16 mL) at room temperature. The mixture was stirred for one hour at room temperature and then quenched with methanol (5 mL). Sodium borohydride (237 mg, 6.27 mmol) was added. The reaction mixture was stirred for one hour, quenched with 1N HCl (1.5 mL) and stirred for 20 minutes. Next, the mixture was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2×). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a tan oil (680 mg, 81%). ESI-MS m/z [M+H]+ calc'd for C11H14BrN3, 268. found 268.