Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C[N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)CCCC1.C([Li])CCC.[CH:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:28]
Reactant: O=Cc1ccccc1
Reactant: c1ccc2c(c1)ncn2CN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1nc2ccccc2[nH]1
Reaction time: 0.25 h

Procedure:
To a solution of 1-pyrrolidin-1-ylmethyl-1H-benzimidazole (5 g) in tetrahydrofurane (20 mL) cooled at a temperature close to −80° C., is added a 2.5M solution of butyl lithium in hexanes (10 mL). The mixture is stirred for 15 minutes. A solution of benzaldehyde (2.64 g) in tetrahydrofurane (20 mL) is added. The mixture is stirred at a temperature close to −80° C. for 1 hour, then at a temperature close to −20° C. for 2 hours. The reaction is quenched by addition of saturated ammonium chloride. The mixture is extracted with ethyl acetate. Pooled extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give (1H-benzimidazol-2-yl)phenylmethanol used without further purification.
Reaction SMILES: O.[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH2:18]3)[CH2:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)N1CCC[C@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(c1ccccc1)N1CCC[C@H](CN2CCNCC2)C1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Water (5 ml), 10% palladium on carbon (900 mg) and ethanol (50 ml) were added to benzyl 4-{[(3R)-1-phenylethylpiperidin-3-yl]methyl}piperazine-1-carboxylate (950 mg) under an argon atmosphere. The mixture was stirred overnight under a hydrogen filled balloon. The catalyst was remove by filtration through celite and the filtrate concentrated in vacuo and azeotroped once with toluene to give 1-{[(3R)-1-phenylethylpiperidin-3-yl]methyl}piperazine as a yellow oil (650 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[CH2:21]([C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step C, except using 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. NMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][C:10]=2[C:27]([F:30])([F:29])[F:28])[CH:7]=1.[OH:31]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:26])=[O:31])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[CH:11][C:10]=2[C:27]([F:28])([F:30])[F:29])[CH:7]=1
Reactant: CSc1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)c1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-(3-chloro-5-pyridyloxy)-5-(4-methylthiobenzenesulfonamido)benzotrifluoride (0.21 g) in acetone (5 mL) was added Oxone™ (0.136 g) in water (1 mL). After 5 hr, the reaction mixture is filtered, and the filtrate is diluted in methylene chloride and extracted with water. The solids from the organic extract were purified by silica chromatography. Trituration with hexane gave the title sulfoxide (0.144 g) as a white solid. mp 156-159° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([F:16])[CH:9]1[CH2:10][N:11]([C:17](OCC)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([F:16])[CH:9]1[CH2:10][N:11]([CH3:17])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CC2N(Cc3ccccc3)CCC2(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CC2N(Cc3ccccc3)CCC2(F)C1
Reaction time: 8 h

Procedure:
A solution of 16.4 g (49.4 mmol, 88%) of ethyl 2-benzyl-5-fluoro-2,7-diazabicyclo[3.3.0)octane-7-carboxylate in 25 ml of absolute tetrahydrofuran is added dropwise to 4.3 g (0.11 mol) of lithium aluminium hydride in 125 ml of absolute tetrahydrofuran, and the mixture is subsequently refluxed overnight. The mixture is decomposed in succession with in each case 4.5 ml of water, 15% strength potassium hydroxide solution and water, and the inorganic salts are filtered off with suction and extracted three times by boiling with 50 ml portions of tetrahydrofuran. The organic solutions are concentrated, and the residue is distilled.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.[CH3:59][N:60](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([C:59]#[N:60])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:12]=2)[C:7]([CH3:19])=[N:6]1
Reactant: CN(C)C=O
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CCC(=O)O)ccc12
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1nn(Cc2c(Cl)cccc2C#N)c2cc(CCC(=O)O)ccc12

Procedure:
To a solution of the compound [122] (29.7 mg) in N,N-dimethylformamide (0.8 mL) were added zinc cyanide (4.8 mg), tris(dibenzylideneacetone)dipalladium(0) (3.7 mg) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (7.8 mg) at room temperature, and then the reaction mixture was subjected to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate, and then the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography to give the titled compound (13.3 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:15]=1[CH3:31].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:15]=3[CH3:31])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (200 mg, 0.88 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (240 mg, 0.88 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.22 mL, 0.88 mmol) in NMP (1.0 mL) and heating at 150° C. for 3 h in the microwave. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a yellow film. Mass Spectrum (ESI) m/e=463 [(M+1) (79Br)] and 465 [(M+1) (81Br)].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:20])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.[H-].[Na+].[CH3:23]I.[Cl-].[Li+]>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:20][CH3:23])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2cccc(F)c2F)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(F)c2F)CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 134.2 %

Procedure:
To a solution of tert-butyl 3-(2,3-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (1.1 g, 3.86 mmol) in N,N-dimethylformamide (15 mL), was added sodium hydride (60% dispersion in mineral oil, 0.31 g, 7.7 mmol). The mixture was stirred for 20 min and methyliodide (0.29 mL, 4.63 mmol) was added. The mixture was stirred for 30 min, aqueous lithium chloride (50 ml, 5%) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated to give the title compound (1.55 g). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 223 (21), 169 (62), 140 (49), 57 (bp).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:14][N:15]=1
Reactant: C1COCCN1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2N2CCOCC2)o1
Yield: 90 %

Procedure:
As described for example 106, 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) using morpholine instead of dimethylamine hydrochloride and potassium carbonate was converted to the title compound (100 mg, 90%) which was obtained as an off-white solid. MS: m/e=490.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:5]([NH:7][C@H:8]([C:19]1[N:23]2[C:24]3[S:38][C:37]([CH2:39][CH3:40])=[CH:36][C:25]=3[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])=[N:27][CH2:28][C:22]2=[N:21][N:20]=1)[CH2:9][C:10]([O:12]C1CCCCC1)=[O:11])=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:5]([NH:7][C@H:8]([C:19]1[N:23]2[C:24]3[S:38][C:37]([CH2:39][CH3:40])=[CH:36][C:25]=3[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])=[N:27][CH2:28][C:22]2=[N:21][N:20]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCc1cc2c(s1)-n1c(nnc1[C@H](CC(=O)OC1CCCCC1)NC(=O)c1ccc(Cl)c(Cl)c1)CN=C2c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc2c(s1)-n1c(nnc1[C@H](CC(=O)O)NC(=O)c1ccc(Cl)c(Cl)c1)CN=C2c1ccccc1Cl
Reaction time: 3 h
Yield: 27.3 %

Procedure:
Cyclohexyl (S)-(+)-3-(3,4-dichlorobenzoylamino)-3-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)propionate (0.40 g) obtained in Example 270 was dissolved in methanol (5 ml). A 2N aqueous sodium hydroxide solution (0.6 ml) was added, and the mixture was stirred for 3 hours. The solvent was evaporated. Water was added and the mixture was washed with ethyl acetate. Citric acid was added to the aqueous layer to make the layer acidic. The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of chloroform, methanol and acetic acid as an eluent to give 96 mg of (S)-(+)-3-(3,4-dichlorobenzoylamino)-3-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)propionic acid.
Reaction SMILES: [CH3:1][Li].Cl[C:4]([C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[C:12]([O:14][CH3:15])=[O:13])=[O:5].CO.[Cl-].[NH4+]>CCOCC.[Cu]I>[C:4]([C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[C:12]([O:14][CH3:15])=[O:13])(=[O:5])[CH3:1]
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)Cl
Reactant: [Li]C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H]1CC=CC[C@H]1C(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1 ml of dry ether was added to 141 mg of copper (I) iodide in a stream of nitrogen gas, and 1.35 ml of ether solution (1.1M) of a methyllithium was added dropwise to the mixture while cooling it by ice. The mixture was cooled down to -78° C. To the reaction mixture was added a solution of (1S, 2R)-2-chloroformyl-1-methoxycarbonylcyclohex-4-ene (50 mg) prepared by a method similar to that of Example 1 in ether (0.5 ml) at -70° C., and the mixture was stirred for one hour. After addition of methanol, the mixture was allowed to stand to return to room temperature, a saturated ammonium chloride solution was then added, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ether, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85) to be purified, and thus 35 mg of the titled compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][N:7]([C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:13]=3[CH3:22])[C:6](=[O:23])[N:5]([CH3:24])[C:4]=2[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:18][C:16]1[C:15]([F:21])=[CH:14][C:13]([CH3:22])=[C:12]([N:7]2[CH2:8][C:9]3[CH:10]=[N:11][C:2]([Cl:1])=[CH:3][C:4]=3[N:5]([CH3:24])[C:6]2=[O:23])[CH:17]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1N1Cc2cnc(Cl)cc2N(C)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(F)c(N)cc1N1Cc2cnc(Cl)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
Zn Dust (0.575 g, 8.80 mmol) was added to a suspension of 7-chloro-3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (0.309 g, 0.880 mmol) and NH4Cl (0.471 g, 8.80 mmol in MeOH/THF (1:1, 16 mL) and the mixture was stirred 1.5 h at RT. The mixture was filtered through Celite, rinsing forward with MeOH and the filtrates were concentrated, diluted with brine and extracted with THF (2×). The combined organics layers were washed with brine, dried (MgSO4), and concentrated to afford 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (0.260 g, 92% yield). MS (ESI) m/z: 321.0 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[N+:27]([C:30]1[C:35]2=[N:36][O:37][N:38]=[C:34]2[C:33](N)=[CH:32][CH:31]=1)([O-:29])=[O:28].O>C1COCC1>[CH3:7][CH:5]([CH3:6])[CH2:4][C@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26]2)[N:12]=1)=[O:10])[CH2:2][NH:1][C:33]1[C:34]2=[N:38][O:37][N:36]=[C:35]2[C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Nc1ccc([N+](=O)[O-])c2nonc12
Reactant: CC(C)C[C@@H](CN)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CNc1ccc([N+](=O)[O-])c2nonc12)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-aminomethyl-3-methyl-butyl)-amide (30 mg, 83.2 μmol) in THF (555 μl) was added 7-nitro-2,1,3-benzoxadiazol-4-amine (CAN 10199-91-4, 19.9 mg, 100 μmol). The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring at reflux temperature for 2 hours. After cooling to room temperature the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with brine; and the aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The black, solid residue was purified by flash chromatography (basic silica gel, 10 g, 0% to 100% ethyl acetate in a 1:1 mixture of dichloromethane and heptane) to give the title compound (25 mg, 57%) as brown solid; LC-MS (UV peak area/ESI) 100%, 524.2609 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]([CH2:10][OH:11])([CH2:8]O)[CH2:6][OH:7])[CH2:4][CH2:3][CH2:2]1.C(=O)(OCC)OCC.[OH-].[K+]>>[CH:1]1([C:5]2([CH2:6][OH:7])[CH2:8][O:11][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OCC(CO)(CO)C1CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(=O)OCC
Product: OCC1(C2CCC2)COC1

Procedure:
A mixture of 2-cyclobutyl-2-hydroxymethylpropane-1,3-diol (6.7 g, 42 mmol), diethyl carbonate (5.5 g, 46 mmol) and potassium hydroxide (0.1 g in 5 ml dry ethanol) was heated to reflux under nitrogen for 15 minutes. Ethanol was then distilled off at atmospheric pressure and the residue distilled under reduced pressure. 3-Cyclobutyl-3-hydroxymethyloxetane was obtained as a colourless liquid (4.3 g, 73%) bp 130°-160° C. at 30 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.[C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:28](=[O:30])[CH3:29])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(N)C4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCCNC1CCCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)C1

Procedure:
The preparation is carried out analogously to FS401 starting from 94 mg (0.46 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-3-ylamine and 45 μl of bromobutyl acetate using 2 equiv. of potassium carbonate.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](#[N:20])[CH2:17][C:18]#[N:19].CCN(C(C)C)C(C)C>O=S(Cl)Cl.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[C:17]([C:16]#[N:20])[C:18]#[N:19])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Reactant: N#CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 827.3 %

Procedure:
A solution of 1-benzyl-1H-pyrazole-4-carboxylic acid (25.0 g, 123.8 mmol) in SOCl2 (250 mL) was heated to reflux for 3 hr. The mixture was concentrated in vacuum to give the intermediate, which was used in the next step without further purification. To a solution of propanedinitrile (8.2 g, 12.8 mmol), DIEA (32.0 g, 247.6 mmol) in THF (250 mL) was added dropwise a solution of intermediate in toluene (250 mL) at 0-5° C. over 1 hr. The resultant mixture was allowed to warm to RT and stirred for 16 hr. The reaction was quenched with water (500 mL) and extracted with EA (500 mL×3), The organic layers were washed with 3 N HCl (500 mL), brine (500 mL×3), dried over Na2SO4 and concentrated to give the crude product (26.5 g, 85.0%) as a yellow solid. MS (ESI) m/e [M+1]+ 250.9.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:14][C:13]([CH:15]=[O:16])=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H][H]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc(-c2ccc(CO)[se]2)c(F)c1F
Reaction time: 0.08 h

Procedure:
3.9 g (12.4 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde as a suspension in 100 ml of diethyl ether are added slowly to a suspension of 0.47 g (12.4 mmol) of lithium aluminium hydride in 20 ml of diethyl ether with ice-cooling. When the addition is complete, the mixture is stirred for 5 min, and water is added dropwise to the mixture until evolution of hydrogen no longer occurs. The mixture is filtered through Celite with MTBE. The filtrate is washed with water and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (yellowish crystals) is used directly for the subsequent reaction.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1.O>CS(C)=O>[NH:1]([CH:8]=[C:9]([CH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH3:15])[CH:17]=1)[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCNc1ccccc1
Reactant: Cn1cc(C=O)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(CC(C#N)=CNc2ccccc2)c2ccccc21
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
To a solution under nitrogen of 6.5 g (0.044 mole) of 3-anilinopropionitrile in 20 mL of dimethylsulfoxide was added 2.4 g (0.044 mole) of sodium methoxide. After stirring for 5 min, 6.5 g (0.41 mole) of 1-methylindole-3-carboxaldehyde. (E. Wenkert, J. H. Udelhofen and N. K. Bhattacharya, J. Am. Chem. Soc., 1959, 81, 3763) was added to the mixture which was then heated at 135° for 30 min, followed by cooling and dilution with 200 mL of water. The resulting solid was collected, resuspended in 150 mL of water and collected again giving 9.14 g (78%) of the title compound; the structure was confirmed by 1H-NMR.
Reaction SMILES: N#N.[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][OH:19])[O:16][CH:17]=2)[CH2:11][CH2:12]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)OC1(c2coc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC1(c2coc(CO)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-4-yl)cyclopropyl pivalate (450 mg, 1.27 mmol) in THF (13.0 mL) at 0° C. was treated with TBAF (2.55 ml of a 1M solution in THF, 2.55 mmol) and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with EA (30 mL), the layers were separated and the org. layer was washed sequentially with sat. aq. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:1 hept-EA)=0.29. LC-MS-conditions 06: tR=0.69 min, [M+H]+=240.11.