Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[C:4]1([CH2:10][CH2:11][CH2:12]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br-].C([O:17][P:18](Cl)[O:19]CC)C.C1(CCC[Mg]Br)C=CC=CC=1>C(OCC)C.O>[C:4]1([CH2:10][CH2:11][CH2:12][PH:18](=[O:17])[OH:19])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(Cl)OCC
Reactant: BrCCCc1ccccc1
Agent: Br[Mg]CCCc1ccccc1
Agent: II
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Product: O=[PH](O)CCCc1ccccc1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
Magnesium turnings (2.44 g, 0.10 mol) in 20 mL of dry diethyl ether under an atmosphere of nitrogen was added several iodine crystals. Phenylpropyl bromide (20.0 g, 0.10 mol) in 80 mL of diethyl ether was placed in a dropping funnel. Approximately 10 mL of the bromide solution was added to the magnesium turnings and stirring was initiated. After several minutes the iodine was consumed and additional phenylpropyl bromide was added while maintaining a temperature of 35° C. Once additional was complete (1.5 hours) the mixture was sealed and stored at 5° C. Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenylpropylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et2O) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and was stirred an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. To the liquid was added 20 mL of water followed by 0.5 ml of concentrated hydrlochloric acid. An exothermic reaction was observed and stirring continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. To the clear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give 3-phenylpropylphosphinic acid (1,R=CH2CH2CH2Ph,R1=H)(9.8 g, 53%) as a clear and colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[O:6][CH2:5]2.[Li+].CCC[CH2-].[CH3:25][C:26]([N:30]1[CH2:40][CH2:39][C:33]2([C:37](=[O:38])[NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31]1)([CH3:29])[CH:27]=[O:28]>O1CCCC1>[Si:12]([O:11][CH:7]1[C:8]2[C:4](=[C:3]([CH3:19])[C:2]([CH:27]([OH:28])[C:26]([N:30]3[CH2:40][CH2:39][C:33]4([C:37](=[O:38])[NH:36][CH2:35][CH2:34]4)[CH2:32][CH2:31]3)([CH3:29])[CH3:25])=[CH:10][CH:9]=2)[CH2:5][O:6]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C=O)N1CCC2(CCNC2=O)CC1
Reactant: Cc1c(Br)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)(C)N2CCC3(CCNC3=O)CC2)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of ((5-bromo-4-methyl-1,3-dihydroisobenzofuran-1-yl)oxy)(tert-butyl)dimethylsilan (3.9 g, 11.36 mmol) in tetrahydrofuran (50 ml) at −78° C. was added N-butyllithium (5.00 ml, 12.50 mmol). After 15 min, 2-methyl-2-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propanal (0.892 g, 3.98 mmol) was added in one portion. The resulting solution was stirred at −78° C. for 3.5 h before being quenched by addition of methanol (6 mL) and saturated sodium bicarbonate (100 mL). The mixture was extracted with 30% isopropanol/methylene chloride (3×100 mL). The combined organic phase was dried over sodium sulfate, concentrated and the residue was purified on silica gel using methanol/methylene chloride to give the title compound. LC/MS: (M+1)+: 489.15.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]3=[N:9][C:8]=2[CH3:17])=[CH:4][C:3]=1[N+:20]([O-])=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:20][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:2]=1[OH:1])[CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[CH3:17]
Reactant: [H][H]
Reactant: Cc1ccn2c(Cc3ccc(O)c([N+](=O)[O-])c3)c(C)nc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccn2c(Cc3ccc(O)c(N)c3)c(C)nc2c1
Yield: 70.8 %

Procedure:
A mixture of 3-(4-hydroxy-3-nitrobenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (2.2 g) in ethanol (100 ml) and tetrahydrofuran (50 ml) was hydrogenated over 10% palladium on carbon (0.7 g) under atmospheric pressure of hydrogen gas for 5 hours at ambient temperature. The catalyst was removed by filtration and filtrate was concentrated in vacuo and the precipitate was collected by filtration to give 3-(3-amino-4-hydroxybenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C([O:15][C:16]1[C:17](=[O:48])[C:18](=O)[C:19]=1[NH:20][C:21]1[CH:22]=[N:23][N:24]([CH3:46])[C:25]=1[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C.C(N(CC)CC)C.C(OCC)C>C(O)C.CCCCCC>[CH3:46][N:24]1[C:25]([NH:26][C:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:21]([NH:20][C:19]2[C:16](=[O:15])[C:17](=[O:48])[C:18]=2[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:22]=[N:23]1
Reactant: CCOc1c(Nc2cnn(C)c2NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCO
Product: Cn1ncc(Nc2c(NCCCNC(=O)OC(C)(C)C)c(=O)c2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 927.7 %

Procedure:
To a suspension of tert-butyl 3-aminopropylcarbamate (366 mg) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (67.0 mg) in ethanol (30 ml) was added triethylamine (0.195 ml), and the mixture was stirred under reflux for 3 hours. To the reaction mixture were added diethyl ether (40 ml) and hexane (10 ml). The crystalline precipitate was collected by filtration and dried in vacuo to give tert-butyl {3-[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl}carbamate (788 mg) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2[C:26](=[CH:27]C=CC=2)[C:25]2([C:35]3=CC4OCOC=4C=[C:34]3OC2)C1=O.BrCCCCC.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[CH2:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:26][CH2:25][CH2:35][CH3:34]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Solvent: CCCCCBr
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-bromopentane to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (91%) as a colorless solid: mp 129-130° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.29 (ddd, J=8.0, 7.7, 1.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.21 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.63 (d, J=9.0 Hz, 1H), 4.23-4.17 (m, 2H), 4.14-4.09 (m, 2H), 3.87-3.77 (m, 1H), 3.72-3.62 (m, 1H), 1.77-1.68 (m, 2H), 1.45-1.30 (m, 4H), 0.91 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.3, 144.6, 142.5, 138.3, 132.7, 128.9, 124.0, 123.2, 121.3, 111.6, 108.7, 99.4, 80.2, 64.6, 64.0, 58.1, 40.4, 29.1, 27.2, 22.4, 14.1; MS (ES+) m/z 366.0 (M+1).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:16](=[CH:17][C:18]=1[CH3:19])[CH:8]1[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:7]1[CH2:6]2.B(Br)(Br)Br.O>ClCCl.C(O)C>[OH:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:16](=[CH:17][C:18]=1[CH3:19])[C@H:8]1[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C@H:7]1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)CC1c3ccccc3NC21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc2c(c(C)c1O)C[C@@H]1c3ccccc3N[C@H]21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under anhydrous conditions, 4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole (76 mg, 0.29 mmol) was dissolved in dry dichloromethane (DCM, 1 cm3) into which a small amount of ethanol had been added. The solution was cooled to -78° C., and a solution of boron tribromide in DCM (0.5 cm3 of 1M solution) added. The reaction was slowly warmed to room temperature, reaction occurring at 0° C. After 30 minutes at 10° C., water (1 cm3) was added cautiously, and the reaction stirred for 15 minutes. The mostly solid material was exhaustively extracted between DCM and a saturated solution of sodium bicarbonate. The DCM layer was dried (Na2SO4), and filtered through a pad of flash silica to yield a colourless solid. Yield: 73 mg, 100% .M.p. 178°-180° (dec). 1H NMR (CDCl3) δ: 7.16 (1H, d, J = 7.3 Hz), 6.99 (1H, ddm), 6.94 (1H, s), 6.73 (1H, ddm, J=7.3, 1.1 Hz), 6.60 (1H, d, J=7.7 Hz), 5.20 (1H, d, J=8.4 Hz), 4.4 (2H, br), 4.15 (1H, ddm), 3.38 (1H, dd, J=16.1, 8.3 Hz), 3.09 (1H, dd, J=16.2 Hz), 2.21 (3H, s), 2.12 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)c2ccncc2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=353.1, tR (minutes, Method F)=1.62
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14].C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>C1COCC1.O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[C:9]([F:13])[C:8]=1[F:14]
Reactant: Fc1cccc(Cl)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A 2.5 M solution of n-butyllithium (2.69 ml, 6.73 mmol) in hexanes was added dropwise to a solution of 1-chloro-2,3-difluorobenzene (1 g, 6.73 mmol) in THF (25 mL) cooled to −78° C. After 45 minutes at −78° C., 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (1.253 g, 6.73 mmol) was added dropwise after which the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with water and ethyl acetate and the organic phase was extracted twice with water. The aqueous extracts were combined and acidified with 12N HCl to pH 3. The product was then extracted with ethyl acetate. The organic phase was dried and concentrated under vacuum to yield the title compound as an oil product (0.93 g, 50% yield): 1H NMR (CDCl3): δ 7.42 (m, 1H), 7.17 (m, 1H), 1.37 (s, 12H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[ClH:28].[ClH:28].[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][CH2:4][CH2:3][N:2]([CH3:27])[CH3:1])[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: CN(C)CCNCC1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCNCC1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a sample of tert-butyl {4-[4-({[2-(dimethylamino)ethyl]amino}methyl)piperidin-1-yl]phenyl}carbamate (approximately 1.0 mmol) is added hydrogen chloride solution (4 N in dioxane (10 mL). After stirring overnight at room temperature, the solvent is evaporated under reduced pressure. The solid material is collected, washed with diethyl ether, and dried under house vacuum to give the intermediate N-[1-(4-amino-phenyl)-piperidin-4-ylmethyl]-N′,N′-dimethyl-ethane-1,2-diamine tetrahydrochloride (0.29 g, 69%), which is used in the following step without further purification.
Reaction SMILES: [C:1]([C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)#[N:2].[CH2:24]1[O:35][C:34]2[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][C:26]=2[O:25]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C:1]([C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:30][CH2:29][C:28]1[CH:32]=[CH:33][C:34]2[O:35][CH2:24][O:25][C:26]=2[CH:27]=1)#[N:2]
Reactant: N#CC(CCC1CCCCN1)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: N#CC(CCC1CCCCN1CCc1ccc2c(c1)OCO2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 9.3 %

Procedure:
A mixture of 2-(3-cyano-3,3-diphenylpropyl)piperidine (217 mg, 0.74 mmol--see Preparation 18), 3,4-methylenedioxyphenethyl bromide (186 mg, 0.82 mmol--see Preparation 12), potassium carbonate (1.0 g) and sodium iodide (20 mg) in acetonitrile (10 ml) was heated under reflux for 48 hours, allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (31 mg, 9%) as a colourless oil, which was characterised as containing 0.75 of an equivalent of water.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[C:13]1([S:19]([N:22]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]2[C:31](OC)=[O:32])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[C:13]1([S:19]([N:22]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[C:23]2[C:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[O:32])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Reactant: Cc1ccccc1N
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 221.2 %

Procedure:
In a three-necked round-bottom flask o-toluidine (0.53 g, 5 mmol) was dissolved in 15 mL of toluene under inert atmosphere. To this solution was added trimethy aluminium (2.5 mL, 5 mmol) and the mixture was stirred at room temperature during 10 minutes. Afterwards, a solution of methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (207 mg, 0.62 mmol) in 15 mL of toluene were added and the reaction mixtures was heated at 80° C. over night. Next, the mixture was allowed to cool to room temperature and 2-3 mL of water were added to hydrolyze unreacted trimethyl aluminium and a 0,5M aqueous solution of disodium tartrate dihydrate were added stirring for a while. Afterwards, the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with the same 0,5M aqueous solution of disodium tartrate dihydrate (25 mL), water and brine, dried and concentrated in vacuum to afford 560 mg of a residue that was used in the following step without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=O)=O.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:20]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)#[N:21]
Reactant: [C-]#N
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)nc1C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#N)nc1C(F)(F)F
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen and with stirring, a solution of 0.596 g of ethyl 6-methylsulfonyl-2-trifluoromethylpyridin-3-ylcarboxylate in 5 ml of dimethylformamide is treated with 160 mg of solid potassium cyanide and a spatula tipful of 18-crown-6, and the mixture is heated at 80° C. for 3 hours. The mixture is cooled overnight, and the next day another 30 mg of potassium cyanide are added and the mixture is heated further until the starting material has disappeared (approximately 2 hours). The mixture is then cooled, added to ice-water and extracted with ethyl acetate. The extracts are washed with water, dried, evaporated and freed from traces of dimethylformamide under high vacuum at approximately 40° C. This gives 480 mg (yield virtually quantitative) of ethyl 6-cyano-2-trifluoromethylpyridin-3-ylcarboxylate in the form of an oil which slowly solidifies. 1H NMR (CDCl3, ppm): 8.29 (1H,d); 7.97 (1H,d); 4.48 (2H, d); 1.43 (3H,t).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7][C@H:6]1[N:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][C:31]1=[O:37])(=O)C.CO>N>[NH2:36][C:33]1[CH:34]=[CH:35][N:30]([C@H:6]2[C@@H:5]([OH:4])[C@H:9]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@:8]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH:18]([F:19])[F:20])[O:7]2)[C:31](=[O:37])[N:32]=1
Reactant: CC(=O)O[C@@H]1[C@H](n2ccc(N)nc2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: N
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)n1

Procedure:
A solution of compound 36 (0.112 g, 0.21 mmol) in NH3.MeOH (4 mL) was stirred at 60° C. for 12 h and then cooled and evaporated to dryness under reduced pressure to give 37 as a white solid. LC-MS: (M+H)+=474.2
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1>C(#N)C>[Cl:1][C:26]1[CH:25]=[C:24]([O:27][CH3:28])[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][C:21]=1[CH2:20][N:12]([CH:9]1[CH2:11][CH2:10]1)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)ccc1OC
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c(Cl)cc1OC
Temperature: 75 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
N-Chlorosuccinimide (110 mg) was added to a solution of tert-butyl cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]carbamate (300 mg) in acetonitrile (5.0 ml) under ice cooling and the mixture was stirred at room temperature for an hour and at 75° C. for 5 hours. The reaction mixture was concentrated in vacuo and the resulted residue was purified with a NH-silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1 to 3/1) to give tert-butyl [2-chloro-4-methoxy-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate (265 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:25]1([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH2:2]2)[CH2:27][CH2:26]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(NCC2CN(C3CC3)CCO2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 369B (0.633 g) and (1-ethoxycyclopropoxy)trimethylsilane (1.601 mL) in anhydrous methanol (15 mL) and acetic acid (1.717 mL) was refluxed for 30 minutes and allowed to cool to room temperature. Sodium cyanoborohydride (0.377 g) was then added and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness. The residue was mixed with 5% aqueous Na2CO3 solution (25 mL) and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 5% to 10% methanol in dichloromethane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloropyridin-2-carboxylic acid (309 g, 1.96 mol) in anhydrous MeOH (2 L) was slowly added thionyl chloride (299.7 mL, 4.12 mol, 2.1 eq) at room temperature (cloudy solution became clear brown solution during the addition of thionyl chloride). After the addition was complete, the reaction mixture was heated to 50° C. and stirred at this temperature overnight. The solvent and excess thionyl chloride were removed under reduced pressure and the crude product was azeotroped with toluene twice. The resulting solid was transferred to a filter funnel and washed with saturated aqueous NaHCO3 until the filtrate was basic. The resulting solid was dissolved in dichloromethane (2 L) and washed with saturated aqueous NaHCO3. The organics were dried over sodium sulfate, filtered and the filtrate was concentrated to provide the title compound as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].Br[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:15][N:14]1[C:10]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:8])=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[N:13]1
Reactant: O=C1CCCCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ncc([N+](=O)[O-])c1N1CCCCCC1=O
Temperature: 140 °C
Yield: 44.9 %

Procedure:
A mixture of azepan-2-one (136 mg, 1.2 mmol), 5-bromo-1-methyl-4-nitro-1H-pyrazole (206 mg, 1.0 mmol), Xantphos (116 mg, 0.20 mmol) and caesium carbonate (456 mg, 1.40 mmol) in dioxane (4 mL) was degassed by bubbling nitrogen through it for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol) was then added and the mixture degassed for a further 10 min before being heated in the microwave at 140° C. for 3 hours. Water (10 mL) was added and the mixture extracted into EtOAc (3×10 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-2-one as a brown gum (107 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 3.96 (dd, J=15.2, 10.0 Hz, 1H), 3.76 (s, 3H), 3.53 (dd, J=15.2, 7.2 Hz, 1H), 2.82-2.74 (m, 2H), 2.13-1.96 (m, 3H), 1.83-1.67 (m, 3H).