Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C)[C@H:9]([C:13]([NH:15][C@H:16](C(N([C@@H]([C@@H](C)CC)[C@H](OC)CC(O)=O)C)=O)C(C)C)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1)C1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:16][NH:15][C:13](=[O:14])[C@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1200 mg (2.33 mmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(2R,3S,4S)-1-carboxy-2-methoxy-4-methyl-hexan-3-yl]-N-methyl-L-valinamide (intermediate 5) was combined with 910.8 mg (2.33 mmol) benzyl-(2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanoate trifluoroacetic acid salt (intermediate 6), 1327 mg (3.49 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 2027 μL N,N-diisopropylethylamine in 50 mL DMF and stirred for 5 min at RT. Next the solvent was removed in vacuo. The remaining residue was dissolved in ethyl acetate and then extracted with 5% aqueous citric acid solution and saturated sodium bicarbonate solution in succession. The organic phase was separated and concentrated. The residue was purified by preparative HPLC. The product fractions were combined, concentrated and the residue was dried in a high vacuum, yielding 1000 mg (55% of the theoretical) of the benzyl ester intermediate N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-benzyloxy)-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide as a resin.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[C:10]([CH3:23])[N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:5].[OH-].[Na+]>CO>[NH2:27][C:25](=[O:26])[C:24]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH:4]([CH3:5])[C:3]([OH:29])=[O:2])[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[CH3:23])=[O:28]
Reactant: COC(=O)C(C)Oc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OC(C)C(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of 521 mg (1.3 mmol) of dl-2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid methyl ester and 10 mL of 1N NaOH in 30 mL of methanol was heated to maintain reflux for 0.17 hours, cooled to room temperature and stirred for 0.5 hour. The mixture was concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic to pH 2-3 with 1N HCl and extracted with EtOAc. The EtOAc solution was concentrated at reduced pressure and the residue stirred with a EtOAc-ether mixture. The insoluble material was filtered to give 246 mg (50% yield) of dl-2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid, mp, 201°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12](I)[C:11]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1.[CH3:27]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH3:27])[C:11]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: O=c1n(-c2ccc(F)cc2)cc(I)c2nc(COc3ccccc3)cn12
Reactant: CB(O)O
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: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc(F)cc2)c(=O)n2cc(COc3ccccc3)nc12
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.63 mg, 0.0023 mmol) was added to a stirred suspension of 6-(4-fluoro-phenyl)-8-iodo-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (35 mg, 0.076 mmol), methylboronic acid (22.7 mg, 0.38 mmol) and K2CO3 (31.5 mg, 0.23 mmol) in a mixture of 1,4-dioxane (4 mL) and DMF (1 mL) under nitrogen and in a sealed tube. The mixture was stirred at 150° C. for 45 minutes under microwave irradiation. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-fluoro-phenyl)-8-methyl-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (19 mg, 72% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.36 (d, J=1.2 Hz, 3H), 5.22 (s, 2H), 6.92 (d, J=1.2 Hz, 1H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.02 (br. d, J=8.1 Hz, 2H), 7.16-7.24 (m, 2H), 7.27-7.34 (m, 2H), 7.36-7.44 (m, 2H), 7.84 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-chloro-6-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=610.1)=70%.
Reaction SMILES: [N+:1]([C@@H:3]1[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])#[C-:2].C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1.C(O)(=O)C>[CH2:32]([O:31][C:29]([O:26][C:25]([C@:3]1([N+:1]#[C-:2])[C@@H:6]([CH2:7][CH:8]=[CH2:9])[N:5]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:4]1=[O:18])([CH3:27])[CH3:24])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)=O
Reactant: [C-]#[N+][C@H]1C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [C-]#[N+][C@]1(C(C)(C)OC(=O)OCc2ccccc2)C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (198.0 mg) in tetrahydrofuran (3.96 ml) was added dropwise a solution of n-butyl lithium (0.634 ml of 1.51 M solution in hexane) at -78° C. over a period of 5 minutes. After stirring for 15 minutes at -78° C., the reaction mixture was added with a solution of acetone (0.0713 ml) in tetrahydrofuran (0.642 ml) at -78° C. over a period of 5 minutes. After stirring for 25 minutes at -78° C., the reaction mixture was added dropwise with a solution of benzyl chloroformate (0.1274 ml) in tetrahydrofuran (1.15 ml) at -78° C. over a period of 5 minutes. The resulting solution was allowed to warm to 0° C. over a period of 40 minutes and added with acetic acid (0.0639 ml) at 0° C. The solvent was distilled off in vacuo at 0° C. and the residue was dissolved in ethyl acetate (30 ml) and washed with brine, aqueous sodium bicarbonate, brine, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (381.2 mg) was chromatographed on silica gel (11 g) eluting with a mixture of ethyl acetate and hexane (1:10→1:5) to give methyl 2-[(3R,4R)-3-(1-benzyloxycarbonyloxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (221.2 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:17]#[N:18])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N:25]([Sn](C)(C)C)=[N+:26]=[N-:27]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:6]([C:17]1[NH:27][N:26]=[N:25][N:18]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Clc1ccc2nc(N3CCCC3)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 120 °C
Yield: 20.5 %

Procedure:
6-Chloro-4-phenyl-2-pyrrolidin-1-yl-quinoline-3-carbonitrile (25 mg, 74.9 μmol, Eq: 1.00) and azidotrimethyltin (30.8 mg, 150 μmol, Eq: 2) were dissolved in xylene (1 ml) and the reaction mixture was heated to 120° C. for 40 h. The mixture was allowed to cool to RT and the solid was filtered off, washed with boiling toluene and suspended in water. The pH was adjusted to 1 by addition of 0.1N HCl and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried with Na2SO4 and evaporated and the remaining residue was purified by column chromatography (silica gel, DCM/MeOH 9:1) to afford the title compound as yellow solid (5.8 mg). MS (ESI): 377.3 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:17])[CH2:15][CH3:16].C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(=O)=O.CC(C)=O.[C:49]([O:53][C:54]([N:56]1[CH2:62][CH2:61][CH2:60][C@H:57]1[CH:58]=[O:59])=[O:55])([CH3:52])([CH3:51])[CH3:50]>ClCCl>[OH:59][C@@H:58]([C@@H:57]1[CH2:60][CH2:61][CH2:62][N:56]1[C:54]([O:53][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:55])[C@@H:15]([CH3:16])[C:14]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:17]
Reactant: CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CCCC[B+]CCCC
Agent: O=C=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.5 %

Procedure:
In following the procedure of Shioiri et al. (Shioiri, T.; Hayashi, K.; Hamada, Y. Tetrahedron. 49(9), 1993, 1913-1924), to a 0° C. (ice-water bath) solution of (4R,5S)-4-methyl-5-phenyl-3-propionyl-2-oxazolidinone (6.4 g, 27 mmol, Fluka) in dichloromethane (110 mL) is added triethylamine (4.3 mL, 31 mmol). Di-n-butylboron triflate (1.0 M solution in dichloromethane, 29 mL, Aldrich) is added dropwise and the resulting mixture is allowed to stir for 45 minutes at 0° C., then cooled to −78° C. (dry ice/acetone bath). N-(tert-butoxycarbonyl)-L-prolinal (3.1 g, 16 mmol, Omega) is added dropwise as a solution in dichloromethane (16 mL) and the reaction mixture is allowed to stir for 2 hours at −78° C. The reaction vessel is then stored in a 0° C. freezer overnight. The next morning, the reaction mixture is warmed to room temperature over 15 minutes and then quenched by the addition of pH 7 phosphate buffer (55 mL) followed by methanol (80 mL). The mixture is then cooled to 0° C. (ice-water bath) and 30% hydrogen peroxide-methanol (1:2, 96 mL) is added dropwise to keep the internal temperature less than 10° C. After stirring for 1 hour in an ice-water bath, to the reaction mixture is added water (55 mL). Volatiles are removed under reduced pressure and the aqueous residue is extracted thrice with diethyl ether. The combined extracts are washed with 1 M potassium bisulfate solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude viscous pale yellow oil (9.5 g) is purified by flash chromatography (hexanes/ethyl acetate) to give 4.6 g (67%) of a white foam. MS (ES+): (M+H)=433.3
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([OH:12])[CH:5]=1)[CH3:2].[C:15](OCC)(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:22])[O:12]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccc(N(CC)CC)cc2oc1=O

Procedure:
--A solution of 4-diethylamino-2-hydroxy-benzaldehyde (29.8 g, 154 mmol) and diethyl malonate (23.8 ml, 157 mmol) in ethanol (185 ml) was treated with piperidine (1.37 ml, 13.9 mmol) and heated under reflux for 4 h. The solution was allowed to cools then concentrated under reduced pressure to approx. half-volume diluted with ether and washed with water, dilute aq. NaOH and water, dried and evaporated under reduced pressure. Trituration of the residue with EtOH (approx. 15 ml) gave yellow crystals which were recrystallised from EtOAc-light petroleum to give the ester 1 as bright yellow prisms (18 the m.p. 76-77° C. A sample recrystallised a second time had m.p. 77-78° C. (Found: C, 66.4; H, 6.7g N, 4.8. C16H9NO4 requires C, 66.4; H, 6.6; N, 4.8%). The discrepancy with the m.p. (87° C.) reported by Kendal et al. (GB 867,592), together with the sharp m.p. and satisfactory analytical result for the present sample suggests that the digits of the reported value may accidently have been transposed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][C:10]([F:12])([F:11])[F:13])[CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(Br)c(OC(F)(F)F)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cc(OCc2ccccc2)ccc1Br
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a mixture of 4-bromo-3-(trifluoromethoxy)phenol (2.97 g, 11.6 mmol) in DMF (10 mL) was added Cs2CO3 (5.65 g, 17.3 mmol) and benzyl chloride (1.46 mL, 12.7 mmol) at RT. The reaction mixture was stirred overnight then quenched with water and diluted with EtOAc. The organic phase was washed with water (3×), brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Heptane) to afford the title compound as a colorless oil (3.92 g, 98% yield). 1H NMR (METHANOL-d4) δ 7.51 (d, J=9.1 Hz, 1H), 7.40-7.45 (m, 4H), 7.34-7.40 (m, 1H), 6.97 (dd, J=2.5, 1.5 Hz, 1H), 6.82 (dd, J=9.1, 3.0 Hz, 1H), 5.06 (s, 2H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[S:17][C:13]=3[CH:12]=2)[CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CC#N.CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[O:25])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Example 3 (188 mg, 0.50 mmol) was stirred in a mixture of DCM/MeCN/DMA (4:4:2, v/v/v) at rt. Dess-Martin periodinane (254 mg, 0.60 mmol) was added and the mixture was stirred at rt for 30 min before another batch of periodinane (254 mg, 0.60 mmol) was added. The resulting mixture was heated at 55° C. for 4 h, then another batch of periodinane (254 mg, 0.60 mmol) was added and the reaction mixture was heated at 60° C. for 6 h. LCMS showed that the reaction was mostly complete. The mixture was then cooled to rt and partitioned between DCM and 3% aq NaOH, and then the organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes to give (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone (150 mg, 80%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.2, 4.8 Hz, 1H), 8.22 (d, J=7.3 Hz, 1H), 8.09 (dd, J=1.3, 8.1 Hz, 1H), 7.70 (d, J=1.1 Hz, 1H), 7.26-7.35 (m, 2H), 7.19-7.26 (m, 1H), 5.49 (s, 2H), 4.68 (td, J=6.5, 12.8 Hz, 1H), 2.53-2.67 (m, 1H), 2.42 (ddd, J=2.7, 5.9, 12.3 Hz, 1H), 2.30 (d, J=13.4 Hz, 1H), 1.94-2.12 (m, 1H), 1.82 (br s, 2H), 1.38-1.66 (m, 2H). LCMS (ESI) m/z 378 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[I-].[CH3:26][S+](C)(C)=O>>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:16][CH2:17][C:18]4([O:21][CH2:26]4)[CH2:19][CH2:20]3)[C:12]2=[O:22])=[CH:7][CH:6]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O
Agent: [I-]
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCC1(CC2)CO1

Procedure:
The title compound was prepared in analogy to example 346 step 1 from 2-[4.5]decane-1,8-dione (described in example 86 step 1) and trimethylsulfoxonium iodide. White solid (87%). MS (m/e): 356.1 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(N(CC)C(C)C)(C)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][C:22](=[O:23])[CH2:21][Br:20]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(NC(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a stirred solution of 2,4,6-trimethylaniline (1 g, 7.40 mmol) in methylene chloride (25 mL) at -50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound (1.51 g, 80%).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=4)[N:20]=[CH:21][C:16]=3[N:15]=[N:14]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[C:30]([OH:33])(=[O:32])C>C1COCC1.[Zn]>[NH2:1][C:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=4)[N:20]=[CH:21][C:16]=3[N:15]=[N:14]2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5].[CH:30]([O-:33])=[O:32]
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)N=[N+]=[N-])cc4)c3n2)cn1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)N)cc4)c3n2)cn1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of {3-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine (171 mg, 0.44 mmol) and zinc dust (117 mg, 1.79 mmol) in THF (5 ml) is added acetic acid (230 μl, 4.0 mmol) and the mixture is stirred for 16 hours at room temperature. The suspension is quenched with THF/dichloromethane/ethyl acetate. The mixture is filtered with suction and the residue is washed with methanol. The filtrate is evaporated and the residue is purified by preparative HPLC to afford {3-[4-(1-amino-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine (“A148”) formate salt as white powder; HPLC/MS1.32 min (A), [M+H] 364;
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([CH3:11])[C:3]=1Br.[O:13]1C=[CH:16][CH:15]=[CH:14]1.[Li][CH2:19]CCC.CO>C1(C)C=CC=CC=1.O>[Br:10][C:5]1[C:6]([Br:9])=[C:7]([CH3:8])[CH:2]=[C:3]2[C:4]=1[C:11]1([CH3:19])[O:13][CH:14]2[CH:15]=[CH:16]1
Reactant: c1ccoc1
Reactant: [Li]CCCC
Reactant: Cc1c(Br)c(Br)c(C)c(Br)c1Br
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(Br)c1Br)C1(C)C=CC2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 11.2 %

Procedure:
To tetrabromo para-xylene (2.1 g, 5.0 mmol) and furan (4 g, 58.8 mmol) in PhMe (55 mL) at −78° C. was added BuLi (2.2 mL, 2.5M in hexanes, 5.5 mmol) dropwise. The reaction was stirred for two hours at −78° C. and the allowed to warm to rt. After 3 hours, MeOH (2 mL) was added and the reaction mixture was poured into water. The organic layer was separated and the aqueous layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silca gel gave 26 (185 mg, 50%) as a white solid. The spectral data correlates well with the literature values.22
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[NH:13]1[C:17]2[CH:18]=[CH:19][S:20][C:16]=2[C:15]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)=[N:14]1.CO>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:15]1[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[NH:13][N:14]=1)=[CH:29]2)([OH:33])[CH2:31][CH3:32]
Reactant: CCC(=O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1)c1ccccn1
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-bromopyridine (224 mg, 1.42 mmol) in anhydrous tetrahydrofuran (2 mL) is added n-BuLi (1.6 M in hexane, 0.95 mL, 1.52 mmol) at −78° C. under nitrogen. After stirring for 20 minutes, to it is added a solution of 142-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl)-propan-1-one (140 mg, 0.473 mmol, Example 28) in anhydrous tetrahydrofuran (4 mL) drop wise. After 30 minutes, the cooling bath is removed and continued stirring at ambient temp for 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (4 mL) followed by water (4 mL). The reaction mixture is extracted with ethyl acetate (120 mL). Ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (10 g silica gel cartridge, 30-60% ethyl acetate gradient in heptane) afforded product. It is then dissolved with minimum amount of methanol and triturated with water to give 1-pyridin-2-yl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-ol (171 mg, 31%, Example 31) as a beige solid; 1H NMR [(CD3)2SO)]: δ 13.195 (1H, s), 11.417 (1H, s), 8.472 (1H, d), 7.742-7.661 (4H, m) 7.259-7.166 (4H, m), 6.59 (1H, s), 5.697 (1H, s, OH), 2.361 (2H, m), 0.785 (3H, t); LC/MS: 375 (M+H).