Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[C:30]([O:32][CH3:33])=[O:31].C(Cl)CCl.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([O:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]([C:14]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]([O:32][CH3:33])=[O:31])=[O:16])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Reactant: COC(=O)[C@H]1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: COC(=O)[C@H]1CCCCN1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 73.7 %

Procedure:
4-(benzoyloxy)-5-methoxy-2-nitrobenzoic acid (1.70 g, 5.61 mmol), (R)-methyl piperidine-2-carboxylate (1.05 g, 5.84 mmol), EDC (3.90 g, 20.31 mmo) and DIPEA (1.0 ml, 5.75 mmol) was stirred in 20 ml of DMA over night. The mixture was evaporated, diluted with DCM, washed with washed 1M NaH2PO4/NaCl (conc) and 0.1 M NaHCO3/NaCl (conc) separately. The organic solvent layer was separated and dried over MgSO4, filtered, concentrated and purified on SiO2 chromatography eluted with EtAc/DCM (1:15) to afford 1.772 g (74%) of the title product. 1H NMR (CDCl3) 7.69 (s, 1H), 7.40-7.38 (m, 2H), 7.35-7.27 (m, 3H), 6.76 (d, 1H), 5.15 (s, 2H), 3.91 (s, 3H), 3.83 (s, 1H), 3.73 (s, 3H), 3.18 (m, 2H), 1.70 (m 2H), 1.47 (m, 4H); 13C NMR 171.89, 171.33, 155.10, 154.78, 148.32, 135.59, 129.05, 128.74, 127.80, 109.66, 109.58, 109.41, 71.63, 56.92, 52.70, 52.19, 45.70, 39.92, 27.29, 26.35, 21.63; MS m/z+451.2 (M+Na).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17](C3C(C)=NC(C)=CC=3)[OH:18])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[C:40](=O)=[O:41].IC>C1COCC1.C(Cl)Cl.CS(C)=O>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:41][CH3:40])=[O:18])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CI
Product: COC(=O)c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1
Reaction time: 0.08 h

Procedure:
n-BuLi (2.66 M in hexanes, 0.883 mL, 2.35 mmol) was added dropwise over 4 minutes to a stirred solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.01 g, 2.35 mmol, Intermediate 12: step d) in THF (11.5 mL) under argon at ˜−70° C. After an additional minute, a pellet of dry ice (˜4 g, ˜90 mmol) was added to the dark solution, and the flask was quickly resealed, evacuated and flushed with argon. After another minute, the resulting homogeneous yellow reaction was removed from the cold bath and stirred under ambient conditions for 5 minutes, and was then transferred to an ice bath and quenched with iodomethane (0.146 mL, 2.35 mmol) and DMSO (4.6 mL). The clear yellow reaction was stirred at 0° C. for 5 minutes, and was then concentrated to remove the THF at room temperature to provide a thick light yellow slurry. This was treated with Li2CO3 (173 mg, 2.35 mmol) and iodomethane (0.438 mL, 7.03 mmol) and stirred at 40° C. for 30 minutes. The resulting opaque thin slurry was then diluted with DCM (15 mL), washed with water (2×25 mL), dried (Na2SO4), filtered, and concentrated to dryness to provide a white solid. This solid was recrystallized from hot heptane (10 mL), and the globular crystals were filtered and washed with heptane (2×6 mL) to provide the title compound as an off-white powder.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])[CH:3]([CH3:5])[CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)C(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(C)C(C)C)c1
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a stirred solution of 69.12B (0.050 g, 0.2 mmol) in THF (3 mL) at 0° C. was added LAH (0.3 mL, 0.3 mmol, 1.0M). The reaction was stirred for one hour and then 1N NaOH(aq) was added to the mixture. The reaction was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-20% EtOAc in hexanes) to yield 69.12C as a colorless oil (0.011 g, 24% yield).
Reaction SMILES: Cl[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C)C=O>[C:13]([S:15][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:16])[CH3:14]
Reactant: CC([O-])=S
Reactant: O=C(O)[C@H](Cl)Cc1ccccc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
The (2R)-2-chloro-3-phenylpropionic acid obtained in Example 13, 20.0 g (108.0 ml), to a mixture of 16.1 g (141.0 mmol) of potassium thioacetate and 40 ml of dimethylformamide was added dropwise at 0° C. and the mixture was stirred at room temperature for 24 hours. To the reaction mixture were added 60 ml of 6% sodium thiosulfate aqueous solution and 200 ml of toluene. The mixture was then adjusted to pH 1.7 with 35% aqueous hydrochloric acid and, after phase separation, the organic phase was recovered. This organic phase was washed with 60 ml of a 6% aqueous solution of sodium thiosulfate, 60 ml of a saturated aqueous solution of sodium chloride and 60 ml of water. The solvent was distilled off under reduced pressure to give 20.7 g (91.8 mmol, yield 85%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid. The optical purity of the product as determined by the same method as in Example 18 was 98.9% ee (S) (configurational inversion rate 99.1%).
Reaction SMILES: C[O-].[Na+].CC1C=CC(S([CH2:14][N+:15]#[C-:16])(=O)=O)=CC=1.[NH2:17][C:18]1[C:23]2=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=4)=[O:37])=[C:31]([F:49])[CH:30]=3)[C:25]([CH:27]=[O:28])=[CH:26][N:22]2[N:21]=[CH:20][N:19]=1>CCOC(C)=O.CO.C1COCC1>[NH2:17][C:18]1[C:23]2=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=[CH:41][N:40]=4)=[O:37])=[C:31]([F:49])[CH:30]=3)[C:25]([C:27]3[O:28][CH:16]=[N:15][CH:14]=3)=[CH:26][N:22]2[N:21]=[CH:20][N:19]=1
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncnn2cc(-c3cnco3)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
To a solution of THF (10 mL) and MeOH (10 mL) cooled in an ice/water bath was added 0.5 M sodium methoxide in MeOH (0.96 mL, 0.48 mmol) followed by TosMIC (93 mg, 0.48 mmol). The solution was allowed to stir for 5 min and then N-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea (73 mg, 0.16 mmol) was added. The solution was heated to 60° C. for 17 h. The reaction mixture was allowed to cool and was transferred to a separatory funnel, diluted with EtOAc (20 mL), washed with aq saturated NaHCO3 (20 mL) and H2O (20 mL). The aqueous layer was back extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo and purified by flash chromatography 5:4:1 v/v/v DCM/EtOAc/MeOH the resulting purified fractions were combined and evaporated providing 26 mg of the title compound as a white solid (0.052 mmol, yield 33%). 1H-NMR (DMSO-d6) δ 10.18 (s, 1H), 10.16 to 10.12 (br s, 1H), 8.55 to 8.54 (d, J=5.4 Hz, 1H), 8.35 to 8.31 (t, J=8.3 Hz, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39 to 7.36 (m, 2H), 7.23 to 7.21 (d, J=10.4 Hz, 1H), 6.63 (s, 1H); MS [M+H]+=499.0; LCMS RT=2.85 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][NH2:34])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][NH:34][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][N:6]=[C:5]3[Cl:13])[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNc2ccc3c(=O)[nH]nc(Cl)c3c2)CC1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 4-(2-aminomethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (187 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded 4-{2-[(4-chloro-1-oxo-1,2-dihydro-phthalazin-6-ylamino)-methyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester. Deprotection with TFA in DCM yielded the title compound. 4-Chloro-6-(2-piperazin-1-yl-benzylamino)-2H-phthalazin-1-one: 46 mg (16.9%): m/z (M+H)=370.00. 1H-NMR (DMSO-d6) δ: 12.31 (s, 1H), 7.89 (d, 1H), 7.77 (m, 1H), 7.33 (d, 1H), 7.21 (m, 1H), 7.14 (dd, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 6.64 (s, 1H), 4.43 (d, 2H), 2.90 (m, 5H), 2.82 (m, 4H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][C:16]([CH2:18][O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:17])(=[O:13])[CH:10]([CH3:12])[CH3:11].Cl>C(OCC)C>[C:9]([O:14][CH2:15][C:16]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([OH:17])[CH2:18][O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)OCC(=O)COC(=O)C(C)C
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccccc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
Under an atmosphere of argon, 2 ml of diethyl ether was slowly added to 695 mg of magnesium turnings, and then thereto was added dropwise 4 g of bromobenzene dissolved in 10 ml of diethyl ether. The resulting liquid was stirred for 1 hour under refluxing and allowed to cool. That liquid was added dropwise to 50 ml of diethyl ether solution of 3.78 g of 1,3-diisobutyryloxyacetone which was previously cooled to -50° C. After the resulting liquid was stirred at -50° C. for 1 hour, a temperature thereof was gradually raised to room temperature. Then, the reaction mixture was added to 50 ml of 2N aqueous solution of hydrochloric acid at 5° C. or below, and an organic layer was separated and the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layers were combined and washed three times with 1N aqueous solution of sodium hydroxide, washed twice with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 5.5 g of the desired compound.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.NC1CCCCO1.Cl>C(O)C.O>[O:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:23][CH2:24]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: NC1CCCCO1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1ccc(NC2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (126.4 g, 0.68 mol) was dissolved in ethanol (880 mL). Triethylamine (82.6 g, 0.82 mol), 4-aminotetrahydropyran (82.7 g, 0.81 mol) were added in turn dropwise, and after the additions the reaction solution was heated to reflux. After refluxing for 5 h, triethylamine (8.3 g, 82 mmol), aminotetrahydropyran (8.3 g, 81 mmol) were added, and this was refluxed for a further 9 hours. After the reaction mixture was allowed to cool to room temperature, 2N HCl (880 mL) and water (880 mL) were added and after stirring for awhile, the solid obtained was filtered off. This was forced air-dried at 60° C. to yield the title compound (183.3 g, quant.) as a yellow solid.
Reaction SMILES: CC1CCCC(C)(C)C=1C(O)CC=C.[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]=1[CH:24]([OH:29])[CH2:25][C:26]([CH3:28])=[CH2:27]>>[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:22])([CH3:23])[C:17]=1[C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[CH2:27]
Reactant: C=C(C)CC(O)C1=C(C)CCCC1(C)C
Agent: C=CCC(O)C1=C(C)CCCC1(C)C
Product: C=C(C)CC(=O)C1=C(C)CCCC1(C)C

Procedure:
By replacing hereabove 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene with 2,6,6-trimethyl-1-[1-hydroxy-3-methyl-3-butenyl]-1-cyclohexene (nD20 = 1.4939; d420 = 0.9270), 2,6,6-trimethyl-1-[3-methyl-3-butenoyl]-1-cyclohexene was obtained; ndD20 = 1.4862; d420 = 0.9307.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.CCOC(C)=O>C(#N)C.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:31][CH2:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:21]([F:20])[F:32])=[CH:28][CH:27]=2)[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: NCCc1ccc(OC(F)F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1nc(Cl)nc(NCCc2ccc(OC(F)F)cc2)n1
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
A solution of 1.8 g of 2,4-dichloro-6-methoxy-1,3,5-triazine in 40 ml of acetonitrile is cooled on an ice bath, 1.28 ml of DIPEA and then 1.68 g of 2-[4-(difluoromethoxy)phenyl]ethanamine are added and the mixture is stirred for 30 minutes. The reaction mixture is diluted by adding 100 ml of EtOAc and 50 ml of water, the phases are separated by settling, the organic phase is washed with saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. The residue is taken up in DCM, the insoluble matter is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane/EtOAc mixture in a gradient of from (95/5 v/v) to (80/20 v/v). 0.94 g of the expected compound is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:51]=[CH:50][C:36]([O:37][CH2:38][C:39]([NH:42]C(=O)OC(C)(C)C)([CH3:41])[CH3:40])=[CH:35][CH:34]=1)=O>>[NH2:42][C:39]([CH3:41])([CH3:40])[CH2:38][O:37][C:36]1[CH:50]=[CH:51][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:34][CH:35]=1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 74.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (32 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(OP([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26])(=O)OCC)C.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[Br:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:19]=[CH:7]/[C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10]
Reactant: CCOP(=O)(Cc1ccccc1Br)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Yield: 81.3 %

Procedure:
5-Chlorosalicylaldehyde (188 g, 1.2 mol) was added to a solution of (2-bromo-benzyl)-phosphonic acid diethyl ester (369 g, 1.2 mol) in tetrahydrofuran (1500 ml) under nitrogen. A solution of potassium tert-butoxide (300 g, 2.68 mol) in tetrahydrofuran (3000 ml) was added while keeping the temperature at 33° C. After completion of the reaction water (1800 ml) was added followed by 4N HCl (450 ml). The organic layer was washed with sodium carbonate solution (500 ml) and saturated NaCl solution. The organic layer was evaporated under reduced pressure at 50° C. to give trans-2-bromo-5′-chloro-2′-hydroxystilbene (301.9 g, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[CH2:15]([OH:20])[CH2:16][CH2:17][C:18]#[CH:19].CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.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>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:19]#[C:18][CH2:17][CH2:16][CH2:15][OH:20]
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: C#CCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OCCCC#Cc1ccn2c(n1)nc1ccccc12
Temperature: 120 °C
Yield: 55.7 %

Procedure:
A mixture of 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (40 mg, 0.2 mmol), pent-4-yn-1-ol (22 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), DIPEA (50 mg, 0.4 mmol) in 2 mL dioxane was heated at 120° C. for 20 min in a microwave reactor and then cooled to rt. It was diluted with EtOAc (20 mL) and washed with brine (30 mL) and water (2×30 mL) and concentrated. The residue was purified by silica chromatography (EtOAc in DCM, 10% to 100%) to afford 5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pent-4-yn-1-ol as a yellow solid (28 mg, 56%). 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=6.8, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 6.95 (d, J=6.8 Hz, 1H), 3.85 (t, J=6 Hz, 2H), 2.82 (t, J=6.8 Hz, 2H), 1.93 (m, 2H); MS (ESI) m/z [M+H]+252.
Reaction SMILES: I[C:2]1[C:3]([CH2:16][OH:17])=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.[C:18]([C:22]1[CH:26]=[C:25]([NH2:27])[NH:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C1(C)C(C)=CC=CC=1.O.[OH-].[NH4+].CCOC(C)=O.[Cu]I>[NH2:27][C:25]1[N:24]([C:2]2[C:3]([CH2:16][OH:17])=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[CH:6]=2)[N:23]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:26]=1
Reactant: OCc1nn(CCOC2CCCCO2)cc1I
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)nc2CO)n1
Temperature: 150 °C
Yield: 62.5 %

Procedure:
A solution of Intermediate 74d (0.51 g, 1.45 mmol) in xylene (2.4 mL) was treated with 3-(tert-butyl)-1H-pyrazol-5-amine (0.18 g, 1.32 mmol) then potassium carbonate (0.38 g, 2.76 mmol), trans-N,N′-Dimethyl-1,2-cyclohexanediamine (0.037 g, 0.26 mmol) and copper (I) iodide (0.013 g, 0.066 mmol) were added. The mixture was degassed then heated at 150° C. for 4 h using microwave irradiation. Another portion of copper (I) iodide (0.006 g, 0.03 mmol) was added and the reaction mixture heated at 150° C. for a further 2 h using microwave irradiation. The mixture was diluted with water (1 mL), conc. aqueous ammonium hydroxide (1 mL) and EtOAc (1 mL) and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% MeOH in DCM to give the title compound as a dark green gum (0.30 g, 63%). LCMS (Method 3): Rt 2.46 min, m/z 364 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][C:16]([O:19][C:20]([NH:22][CH2:23][C:24](ON1C(=O)CCC1=O)=[O:25])=[O:21])([CH3:18])[CH3:17].[Mn]([O-])(=O)(=O)=O.[K+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.C(Cl)Cl.CO.CO>[OH:4][CH2:3][C@@H:2]([NH:1][C:24](=[O:25])[CH2:23][NH:22][C:20](=[O:21])[O:19][C:16]([CH3:15])([CH3:17])[CH3:18])[CH2:5][CH:6]=[CH2:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: C=CC[C@H](N)CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC[C@@H](CO)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 3 h

Procedure:
In a 5 L reactor, to a solution of (2S)-2-amino-4-penten-1-ol D20 (110 g of the crude title compound prepared in the description D20) in THF (660 ml) and MeOH (440 ml) stirred at 0° C. (+5° C. internal) was added triethylamine (182 ml, 1305 mmol) and 2,5-dioxo-1-pyrrolidinyl N-{[(1,1-dimethylethyl)oxy]carbonyl}glycinate (available from Sigma-Aldrich #15423) (237 g, 870 mmol) portionwise over 15 min. The reaction mixture was stirred at 2° C. (internal temperature) for 3 hours. TLC check (TLC-NH2, DCM/MeOH 95/5, potassium permanganate) showed residual starting material. Further 2,5-dioxo-1-pyrrolidinyl N-{[(1,1-dimethylethyl)oxy]carbonyl}glycinate (60 g, 220 mmol) was added and the mixture stirred at 2° C. for 1 hour. TLC check (TLC-NH2, DCM/MeOH 95/5, potassium permanganate) showed residual starting material. Further 2,5-dioxo-1-pyrrolidinyl N-{[(1,1-dimethylethyl)oxy]carbonyl}glycinate (40 g, 146 mmol) was added and the mixture stirred at 2° C. for 1 hours. TLC check (TLC-NH2, DCM/MeOH 95/5, potassium permanganate) showed residual starting material but the work-up was carried out. The reaction mixture was poured into aqueous saturated solution of NH4Cl (3400 ml) and AcOEt (1375 ml), then the phases were separated and the aqueous layer was back-extracted with AcOEt (1375 ml). The combined organic layers were washed with NaHCO3 aqueous saturated solution (1031 ml) dried (Na2SO4) and evaporated to give crude material (268 g, deep brown). This residue was triturated with Et2O (687 ml) for 1 hour at 25° C. The solid was filtered (gooch n3), washed with Et2O (200 ml) and dried under vacuum to give the title compound D21 (87 g) as pale brown solid. Mother liquors (deep brown) were evaporated and the residue chromatographed (Biotage 75 L, silica column, eluting with DCM/MeOH 98/2, 95/5) to give (34 g) of residual brown product that was triturated with Et2O (200 ml). The solid was filtered, washed with Et2O and dried under vacuum to give a further batch of the title compound D21 (26 g) as pale brown solid. MS: (ES/+) m/z: 259 (M+1). C12H22N2O4 requires 258. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9 H) 2.22-2.43 (m, 2 H) 2.68-2.83 (m, 1 H) 3.50-3.86 (m, 4 H) 3.94-4.09 (m, 1 H) 5.00-5.25 (m, 3 H) 5.64-5.89 (m, 1 H) 6.17-6.44 (m, 1 H)