Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1.P(Br)(Br)[Br:14]>C(OCC)C>[Br:14][CH2:2][C:3]1[S:4][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: CCCCSc1ccc(CO)s1
Solvent: CCOCC
Product: CCCCSc1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of crude 46 (55.4 g, 0.274 mol) in anhydrous ethyl ether (70 mL) was added dropwise to a solution of phosphorus tribromide (12.9 mL, 0.137 mol) in anhydrous ethyl ether (300 mL) at 0° C. After addition was complete, the mixture was allowed to warm slowly to room temperature and stirred for 4 hours under nitrogen. The mixture was then extracted with ethyl ether (3×150 mL). The combined organic solution was washed with brine and dried (MgSO4). MgSO4 was removed by filtration and the crude product was carried to the next step without the removal of solvent to prevent product decomposition.
Reaction SMILES: OC(COC1C=CC=CC=1OC)CN1CCC([N:10]2[CH2:14][CH2:13][N:12](C3C=CC(Cl)=CC=3)C2=O)CC1.[Cl:33][C:34]1[CH:40]=[CH:39][C:37](N)=[CH:36][CH:35]=1.Br.BrCCN>C(C(CC)=O)C>[Cl:33][C:34]1[CH:40]=[CH:39][C:37]([CH:13]([NH2:12])[CH2:14][NH2:10])=[CH:36][CH:35]=1
Reactant: COc1ccccc1OCC(O)CN1CCC(N2CCN(c3ccc(Cl)cc3)C2=O)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: Br
Agent: NCCBr
Solvent: CCC(=O)CC
Product: NCC(N)c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
The 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-ethylamino]-piperidine can be prepared as follows: A mixture of 38 g of p-chloroaniline and 31 g of 2-bromoethylamine-hydrobromide is heated to 70° C. with stirring. After 30 minutes 75 ml of diethyl ketone are added and the mixture is refluxed for 4 hours. The black solution is then concentrated under reduced pressure. The residue is made alkaline with 2 N sodium carbonate solution and extracted with three 100 ml portions of chloroform. The residual oil is fractionally distilled in vacuo to yield 1-(4-chlorophenyl)-ethylenediamine with a boiling point of 130°-135° C. (1.5 torr).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>C(O)CCC.C(Cl)Cl>[F:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Temperature: 100 °C
Yield: 21.5 %

Procedure:
2,4-Dichloropyrimidine (7.0 g, 47 mmol) was dissolved in n-butanol (5 ml), followed by addition of DIPEA (9.0 ml, 51.7 mmol), then 2-fluoro-5-methylaniline (5.3 ml, 47 mmol). The mixture was heated at 100° C. overnight, and then allowed to cool to ambient temperature. The mixture was evaporated to give an oil, which was taken up in DCM (250 ml) and washed with water (3×50 ml), brine (50 ml), dried over MgSO4 and evaporated to give an orange oil. This was purified by column chromatography eluting with EtOAc:isohexane (10:90) to give the title product as a white solid (2.40 g, 21%). NMR (300 MHz): 2.3 (s, 3H), 6.7 (d, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.5 (d, 1H), 8.1 (d, 1H), 9.7 (s, 1H); m/z: (ES+) 237.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.C(N1C=CC=CC1=O)(N1C=CC=CC1=O)=S.[N-:33]=[C:34]=S.[CH3:36][CH:37]([CH3:43])[CH2:38][C:39]([NH:41]N)=[O:40].C(Cl)CCl>C(Cl)Cl>[CH2:38]([C:39]1[O:40][C:34]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[N:33][N:41]=1)[CH:37]([CH3:43])[CH3:36]
Reactant: [N-]=C=S
Reactant: CC(C)CC(=O)NN
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)Cc1nnc(Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (200 mg, 0.91 mmol) in methylene chloride (4.5 ml) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (212 mg, 0.91 mmol) and stirred at room temperature for 1 hour. Upon complete formation of the isothiocyanate, 3-methylbutanehydrazide (159 mg, 1.37 mmol) was added to the mixture and stirred at room temperature for overnight. EDC (315 mg, 1.64 mmol) was then added and the reaction stirred at room temperature for 14 hours. The reaction was concentrated to dryness and taken up in water to form a slurry. The slurry was filtered and washed with water to afford the crude product, which was purified by column chromatography to afford the title compound as off-white solid after drying (217 mg, 69% yield). LC/MS, ESI-MS(+) m/z 344.1, RT 1.45 (Condition R).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C(OCC)(=O)C.C1COCC1>CCO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1(C2CCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(C2CCCC2)CC1

Procedure:
In a 250 mL round bottom flask with a magnetic stirrer, 5.4 g (16.7 mmol) 4-cyclopentyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester was dissolved in 40 mL EtOH. To the colourless solution 40 mL 4N NaOH was added. The orange solution was stirred under reflux for total of 6 days. The ethanol was removed and the reaction mixture was diluted with 100 mL ice water and extracted twice with 100 mL diethyl ether. The aqueous layer was acidified with 60 mL 4 N HCl to pH=2. A white precipitate formed and after addition of 200 mL ethyl acetate: THF 1:1 the white gelatinous suspension was filtered through a membrane filter. The aqueous layer from the filtrate was separated and extracted once with 100 mL ethyl acetate. The organic was layer dried with Na2SO4, filtered and concentrated under vacuum. The crude product (2.54 g, yellow viscous oil) was purified over silica chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 1.89 g (38%) of the title compound as off-white solid. MS ISP (m/e): 298.2 [(M+H)+].
Reaction SMILES: ClC(Cl)C.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[CH:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(#N)C>[CH:8]([C:17]1[N:18]2[C:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][C:16]=1[C:24]([O:26][CH3:27])=[O:25])=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2n(c1)CCCC2
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc2n(c1C=O)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous dichloroethane (20 mL) and anhydrous DMF (0.70 mL, 9.0 mmol). To the mixture at 0° C. was added phosphorus oxychloride (0.70 mL, 7.3 mmol) over a period of 2 min, while maintaining the reaction temperature between 0° C. and 10° C. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. A solution of 193c (1.0 g, 5.6 mmol) in acetonitrile (10 mL) was added and the reaction mixture was stirred at room temperature for 3 hours. After this time, it was concentrated under reduced pressure. The oily residue was taken up with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water (50 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:5 ethyl acetate/petroleum ether to afford 193d as a white solid (703 mg, 58%). MS-ESI: (M+H)+ 208.3. 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 6.40 (s, 1H), 4.27 (t, J=6.0 Hz, 2H), 3.78 (s, 3H), 2.78 (t, J=6.0 Hz, 2H), 1.94-1.85 (m, 2H), 1.78-1.69 (m, 2H).
Reaction SMILES: CCCCCC.[CH3:7][CH:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH2:9]O.[CH2:18]([O:25]COC[C@@H](C)COS(C1C=CC(C)=CC=1)(=O)=O)[C:19]1C=CC=C[CH:20]=1>O>[CH3:7][C@@H:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])/[CH:9]=[CH:20]\[CH2:19][CH2:18][OH:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Reactant: CC(CO)CCCC(C)(C)O
Solvent: O
Solvent: CCCCCC
Product: C[C@H](/C=C\CCO)CCCC(C)(C)O

Procedure:
UV (hexane) λmax 234.0 (ε27 800), 241.0 (ε30 200), 248.5 (sh, ε19 900) nm; 1H NMR (400 Hz, CDCl3) δ0.86 (3H, d, J=6.5 Hz, CH—CH3), 1.21 [6H, s, C(CH3)2], 2.08 (2H, q, J=6.9 Hz, 4′-H2), 2.26 (1H, dd, J=13.1, 7.1 Hz), 2.39(1H, dd, J=13.4, 7.2 Hz), 2.56 (1H, dd, J=13.5, 4.2 Hz), 2.70 (1H, dd, J=13.3, 4.3 Hz), 4.48 (2H, m, 1- and 3-H), 5.10 (2H, s, C═CH2); 5.70 (1H, dt, J=15.0, 6.9 Hz, 3′-H 6.03 (1H, d, J=10.8 Hz, 1′-H), 6.29 (1H, dd, J=15.0, 10.8 Hz, 2′-H); MS (El) m/z (relative intensity) no M+, 318 (M+−H2O, 19), 300 (8), 285 (4), 59 (100); HRMS (ESI) exact mass calculated for C21H34O2 (M+−H2O) 318.2559, measured 318.2570.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]3[CH2:34][CH2:33]O[CH2:31][CH2:30]3)[N:9]=2)[CH:7]=1.[CH3:39][N:40]1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]3[CH2:30][CH2:31][N:40]([CH3:39])[CH2:33][CH2:34]3)[N:9]=2)[CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1cn(C/C=C/CN2CCOCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Product: CN1CCN(C/C=C/Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from 1-methylpiperazine. LCMS (Method 23) [M+H]+=557.1, RT=1.76 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (d, 1H, J=5.2 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=2.4 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.92-5.80 (m, 1H), 5.78-5.66 (m, 1H), 4.81 (d, 2H, J=6.0 Hz), 2.94 (d, 2H, J=6.4 Hz), 2.45-2.20 (m, 8H), 2.13 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](OB(O)O)[CH:17]=[CH:18][C:19]=1[F:20].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: OB(O)Oc1ccc(F)c(F)c1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To 25.0 g of 6-bromo-2-naphthol and 22.0 g of 3,4-difluorophenylboric acid were added 100 ml of toluene, 50 ml of ethanol, 50 ml of a 2 N aqueous solution of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was heated under reflux for 3 hours. The reaction solution was then allowed to cool to room temperature. The resulting organic phase was separated, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified through silica gel column chromatography (dichloromethane) to obtain 25.3 g of 6-(3,4-difluorophenyl)-2-naphthol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[O:20])[CH:12]=1.[CH3:21][C:22]1[N:23]([CH2:29][CH2:30][O:31][CH2:32][C:33](=O)[CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:24]([CH3:28])=[C:25]([CH3:27])[N:26]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:12]2[C:13](=[O:20])[N:14]([CH3:19])[C:15](=[O:18])[N:16]([CH3:17])[C:11]=2[NH:10][C:33]([CH2:32][O:31][CH2:30][CH2:29][N:23]2[C:24]([CH3:28])=[C:25]([CH3:27])[N:26]=[C:22]2[CH3:21])=[C:34]1[C:35]([O:37][CH3:38])=[O:36]
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CC(=O)COCCn1c(C)nc(C)c1C
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Product: COC(=O)C1=C(COCCn2c(C)nc(C)c2C)Nc2c(c(=O)n(C)c(=O)n2C)C1c1ccccc1Cl
Yield: 4 %

Procedure:
The title compound (210 mg) was prepared from 2-chlorobenzaldehyde (1.4 g), 6-amino-1,3-dimethyl-2,4-dioxopyrimidine (1.55 g) and methyl 4-[2-(2,4,5-trimethylimidazol-1-yl)ethoxy]3-oxobutanoate (2.68 g) by the method of Exmaple 1. M.p. 226°-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].C([Mg]Cl)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Mg]Br>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Reactant: Br[Mg]c1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ccc(F)cc1C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a −78° C. solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide (9.40 g, 47.4 mmol) in THF (39.5 mL) was added isopropylmagnesium chloride 2.0M in THF (47.4 mL, 94.8 mmol) at −40° C. The solution was allowed to rise to −10° C. over 40 min then was lowered back to −40° C. in an acetonitrile/dry ice bath. To the cooled mixture was added 2-pyridylmagnesium bromide, 0.25M in THF (209 mL, 52.2 mmol) and the mixture was allowed to warm to rt. After 22 h, the reaction was diluted with DCM (200 mL) and quenched with satd ammonium chloride solution (200 mL). The aq layer was extracted with DCM (2×100 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (2-amino-5-fluorophenyl)(pyridin-2-yl)methanone as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65-8.72 (1H, m), 8.02 (1H, td, J=7.7, 1.8 Hz), 7.79 (1H, dt, J=7.8, 1.0 Hz), 7.60 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.29-7.36 (1H, m), 7.18-7.29 (3H, m), 6.88 (1H, dd, J=9.2, 4.7 Hz); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[O:3]1.C(N(CC)CC)C.[Br:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:12]([CH2:11][C:10]1[C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:37]
Reactant: O=C(Cl)CBr
Reactant: CC1(C)Cc2cccc(CNc3ccccc3Oc3ccccc3)c2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Cc2cccc(CN(C(=O)CBr)c3ccccc3Oc3ccccc3)c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine (0.20 g, 0.58 mmol) dissolved in DCM (2 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and EtOAc (B) (30% B, 80 g, 2.5 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 5 CV, 60 mL/min) to afford 170 mg (63%) of 2-Bromo-N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)acetamide as a colourless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH:11]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[CH:20]=[CH:19]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O>[CH:11]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[C:20]([CH:8]=[O:9])=[CH:19]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1cccc2ccn(CC3CCCCC3)c12
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(C=O)cn(CC3CCCCC3)c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Phosphorous oxychloride (12 ml, 0.13 mol) was added slowly over 30 minutes to dimethylformamide (30 ml) at −10° C. The solution was allowed to warm to 0° C. over 1 h, then 1-(cyclohexyl)methyl-7-methoxy-1H-indole (prepared as in Example 26; 3.2 g, 13 mmol) was added portionwise and the solution stirred at room temperature for 16 h. The solution was cooled in an ice bath and diluted with water, then neutralised carefully with sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The organic extracts were combined and the solvent removed in vacuo. The residue (3.5 g) was dissolved in aqueous sodium hydroxide solution (5 M; 100 ml) and the mixture refluxed at 100° C. for a further 16 h. The solution was cooled and extracted with ethyl acetate (3×50 ml), the organic extracts combined and the solvent removed in vacuo to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (2.2 g, 8.12 mmol) as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:13][CH:14]=1)=[O:3]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC1NC(=O)NN=C1c1ccc(NC=O)cc1
Temperature: 0 °C

Procedure:
With ice-cooling and stirring, acetic anhydride (1.4 ml) was added dropwise to formic acid (0.7 ml) and the mixture was stirred at 50° C. for 15 minutes. This solution was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.28 g) in formic acid (6 ml) with ice-cooling and stirring, followed by further stirring with ice-cooling for 50 minutes. The reaction mixture was poured into ice water and the resulting precipitate was collected by filtration and washed with water. The solid was recrystallized from dimethyl sulfoxide to give 6-(4-formylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.36 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH3:22])=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To the mixture of 2-aminonicotinic acid (2.0 g, 14.5 mmol), methylamine hydrogen chloride (1.47 g, 1.5 eq), EDC (4.49 g, 1.5 eq), HOBt (2.35 g, 1.2 eq) in DMF (20 mL) was added DIEA (7.6 mL, 3.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 2-amino-N-methylnicotinamide (2.16 g, isolated yield ˜98%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOCC3)c2n1
Temperature: 60 °C
Yield: 55.8 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g) and then heated to 60° C. for 1 hour. On cooling to room temperature, to the above was added 4-(2-bromoethyl)tetrahydro-2H-pyran (0.110 g) and the reaction was warmed to 50° C., overnight. The reaction mixture was quenched with water (5 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The separated organic layers were combined and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (111 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:3]=[CH:4]/[CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][C:9]2=[O:13].[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C)C=O>[Si:26]([O:1][CH:2]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[CH:3]=[CH:4]/[CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][C:9]2=[O:13])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: O=C1CCC2C(/C=C/C(O)COc3ccccc3)CCC12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
A mixture of (E)-2-(3-hydroxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one (49 mg), the less polar component prepared as described in Reference Example 45 and in the form of (±)-(E)-2β-(3β-hydroxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one, tert-butyldimethylchlorosilane (31 mg), and imidazole (29 mg) in dimethylformamide (0.116 ml) was stirred at the ambient temperature for 2 hours. The mixture was then treated with water (10 ml) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure, to give (E)-2-(3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one (76 mg), in the form of (±)-(E)-2β-(3β-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one.