Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[CH2:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([CH2:32][CH2:31][CH2:30][N:29]5[S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:35]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCCc2ccc(N)cc21
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5c(c4)N(S(C)(=O)=O)CCC5)nn23)c1

Procedure:
N-tert-Butyl-3-[2-(1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamine in an analogous manner to Example 1052a. Product isolated as a yellow solid (69 mg, 57%). m.p.=187-191° C.; LCMS (m/e) 555 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.50 (s, 1H), 9.04 (s, 1H), 8.51-8.42 (m, 2H), 7.82 (d, 1H, J=7.9 Hz), 7.76-7.65 (m, 3H), 7.62 (s, 1H), 7.20 (d, 1H, J=4.8 Hz), 7.16 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=4.8 Hz), 3.73-3.67 (m, 2H), 3.00 (s, 3H), 2.78-2.71 (m, 2H), 1.97-1.87 (m, 2H), 1.11 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18](Cl)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(-c3cccc(F)c3)n2)c1

Procedure:
The chloro thiazole (114)(80 mg, 0.24 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E, except that the reaction mixture was heated for a total of 12 h. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1>CO.O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:12]2[N:17]=[C:16]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[C:15]([F:19])=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-Aminobenzoic acid (410 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) in methanol (10 mL) and water (1 mL) was stirred at 100° C. for 24 h to yield N2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine after methanol was removal. This residue was redissolved in DMF (10 mL) and to it was added potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.37 mL, 6 mmol), stirred at room temperature overnight, and then diluted with 1 N HCl (80 mL) and ethyl acetate (80 mL). The ethyl acetate layer was washed with 1N HCl (60 mL) and water (60 mL). The organic layer was separated, dried, evaporated and the resulting residue was recrystallized from ethyl acetate/hexanes to give N2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (150 mg, 63%). 1H NMR (acetone-d6): δ 3.85 (s, 3H), 3.88 (s, 3H), 7.88-7.97 (m, 4H), 7.98-8.05 (m, 4H), 8.18 (d, J=3.0 Hz, 1H), 9.00 (br, 1H, NH), 9.04 (br, 1H, NH); LCMS: ret. time: 27.07 min.; purity: 95.54%; MS (m/e): 397.04 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:13](OCC)(=[O:17])[C:14]([O-:16])=[O:15]>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13](=[O:17])[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cccnc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
10 g. (0.063 mol) of 3-bromopyridine in 80 ml. of dry THF was added dropwise to a -70° C. solution of butyl lithium (1.6M, 40.6 ml, 0.065 mol) dissolved in 120 ml. of dried THF over a 20 minute period. The resulting brown solution was stirred at -70° C. for 30 minutes and then transferred by nylon tubing under positive nitrogen pressure into a stirred 0° C. solution of ethyl oxalate (36.8 g, 0.25 mol) in 60 ml of dry THF. The solution was stirred at 0° C. for 45 minutes, quenched by addition of 50 ml. glacial acetic acid, warmed to room temperature and poured into 500 ml of water, adjusted to pH 7.0 with 750 ml saturated sodium bicarbonate and extracted with 2×500 ml ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a brown oil; 24.7 g. This oil was flash chromatographed on silica gel eluted with 1:2 ethyl acetate hexane. A viscous yellow oil was obtained; 1.56 g, m/e 179, spectral data consistent with structure of title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]12[CH2:19][O:18][C@H:17]([CH3:20])[C@H:16]1[C:15](=[O:21])[N:14]([CH3:22])[C:13]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:12]2.[H][H]>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]23[CH2:19][O:18][C@H:17]([CH3:20])[C@H:16]2[C:15](=[O:21])[N:14]([CH3:22])[C:13]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:12]3)[CH:4]=1
Reactant: [H][H]
Reactant: C[C@H]1OC[C@]2(c3cc([N+](=O)[O-])ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1OC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Yield: 100 %

Procedure:
A solution of tert-butyl ((4aS,5R,7aS)-7a-(2-fluoro-5-nitrophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (1.6 g, 3.77 mmol) in ethanol (30 ml) was hydrogenated over 10% Pd/C (200 mg) at RT under a balloon of hydrogen for 4 h. The catalyst was removed by filtration through Celite-washing with ethanol. The filtrate was evaporated to give the title compound (1.48 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J=6.06 Hz, 3H) 1.54 (s, 9H) 3.29 (s, 3H) 3.35 (dd, J=9.22, 1.89 Hz, 1H) 3.63 (s, 2H) 4.25-4.30 (m, 1H) 4.33-4.42 (m, 2H) 6.44 (dd, J=6.32, 2.78 Hz, 1H) 6.56-6.63 (m, 1H) 6.91 (dd, J=10.99, 8.72 Hz, 1H) 10.47 (br. s., 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29]([OH:31])=O)[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:72]=[CH:71][C:66]([C:67]([O:69][CH3:70])=[O:68])=[CH:65][C:64]=1[O:73][CH3:74]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][C:63]([NH:62][C:29]([C@@H:20]2[NH:19][C@@H:18]([CH2:32][C:33]([CH3:36])([CH3:34])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:31])=[C:64]([O:73][CH3:74])[CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (0.28 g, 0.5 mmol), was reacted with diisopropylethylamine (0.38 mL, 2.25 mmol), diphenylphosphinic chloride (0.36 mL, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.09 g, 0.5 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 102 mg, 33%). MS (H+), 610.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]([OH:22])[CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[O:34][N:33]=1>C(O)(C)(C)C>[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]([OH:22])[CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:31][C:32]4[CH:36]=[C:35]([C:37]5[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=5)[O:34][N:33]=4)[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4cc(-c5ccc(C(F)(F)F)cc5)on4)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol hydrochloride (50 mg) in t-butanol at room temperature was added triethylamine (60 μl), and the mixture was stirred at room temperature for 5 minutes. To this mixture was added 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole (26 mg), and the mixture was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of methanol, and purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to afford (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinyl]propan-2-ol, a compound of Formula I.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][C:18]1[C:23](I)=[CH:22][N:21]=[C:20]([N:25]=[CH:26][N:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[N:19]=1>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:23]2[C:18]([Cl:17])=[N:19][C:20]([N:25]=[CH:26][N:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:29])[CH3:30])=[N:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)N(C=Nc1ncc(C#Cc2ccc(Br)cc2)c(Cl)n1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
A mixture of 0.5 g of 1-bromo-4-ethynylbenzene, 5.0 mL of triethylamine, 0.031 mg of copper iodide, 0.94 g of 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine and 0.046 g of dichlorobis(triphenyl)phosphine palladium II was magnetically stirred at room temperature for 18 hrs. The mixture was diluted with acetonitrile, filtered and the filtrate evaporated in vacuo. The evaporated filtrate was dissolved in dichloromethane and loaded on a column of silica gel equilibrated in the same solvent. Cuts were monitored by thin layer chromatography. After initial cuts of brown colored eluates, the product subsequently eluted as yellow fractions. Like cuts were pooled and evaporated to give 0.84 g of 5-(4-bromophenylethynyl)-4-chloro-2-diisopropylaminomethyleneaminopyrimidine as a thick amber syrup.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:16])=[O:15]>O.CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:16])(=[O:2])=[O:15]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CS(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of potassium permanganate (101 mg, 0.64 mmol) in water (1.83 mL) was treated with a solution of 2(R)-(3-chloro-4-methanesulfinyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (191.5 mg, 0.58 mmol) in methanol (5.8 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was diluted with methanol and then was filtered through a pad of celite. The filtrate was concentrated in vacuo and was azeotroped with acetonitrile. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 methylene chloride/methanol with glacial acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (87 mg, 43%) as an off-white foam: EI-HRMS m/e calcd for C15H17ClO5S (M−H2O)+ 326.0379, found 326.0378.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]3)=[N:17][N:16]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(c1nnc(N(C)C3CC(C)(C)NC(C)(C)C3)s1)C2=O
Temperature: 150 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.282 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (132 mg, 0.395 mmol) in DMF (0.7 mL) under nitrogen was added K2CO3 (78 mg, 0.564 mmol) followed by CuI (32 mg, 0.169 mmol). The reaction mixture was heated at 150° C. for ˜18 hours. A further 1.4 eq of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (132 mg, 0.395 mmol) and 0.6 eq of CuI (32 mg, 0.169 mmol) were added and stirring was continued at 150° C. for an additional 48 hours. The reaction mixture was diluted with EtOAc (10 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product as a dark brown oil. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified) collecting at 312 nm. The product containing fractions were combined and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (˜20 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (12 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as a pale yellow/brown glass-like solid (28 mg, 23% yield). LC-MS: Rt 0.91 min; MS m/z 430.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88-7.97 (m, 1H), 6.96-7.03 (m, 2H), 4.35 (t, J=6.57 Hz, 2H), 4.16 (tt, J=12.19, 3.22 Hz, 1H), 3.85 (s, 3H), 3.14 (t, J=6.57 Hz, 2H), 2.91 (s, 3H), 1.58 (dd, J=12.13, 3.03 Hz, 2H), 1.42 (t, J=11.87 Hz, 2H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:22][Si:23]([CH3:37])([CH3:36])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.C([O-])(O)=O.[Na+]>C1COCC1.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+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([C:32]3[N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:37])([CH3:36])[CH3:22])[N:29]=[CH:30][CH:31]=3)[C:3]=2[N:11]=[N:10]1)([O-:21])=[O:20]
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Reactant: C[Si](C)(C)CCOCn1nccc1B(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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2c1nnn2Cc1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
A solution of 7-chloro-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (306 mg, 1 mmol), 1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-ylboronic acid (2 mmol), Pd(PPh3)4 (100 mg) and saturated NaHCO3 (5 mL) in THF (20 mL) was refluxed for 2 h, diluted with water (20 mL), extracted with EtOAc (2×20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2:EtOAc (6:1)] to give 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 34%) as a pale yellow syrup.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: COc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC
Yield: 74.5 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (3.1 mL), 2-methoxycinnamic acid (2.0 g), WSC.HCl (2.1 g), and methylene chloride (100 mL), to give the captioned compound (2.8 g, 76%) as an amorphous solid product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])N(CCCl)CCCl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CO>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([CH:23]1[CH2:22][C:20]([C:19]2[CH:27]=[CH:28][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH2:26][CH2:25][NH:24]1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(Cc2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC(c2ccncc2)(c2ccc(Cl)cc2)CCN1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 0.7 %

Procedure:
Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled in ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed over two minutes by sodium hexamethyldisilazide solution (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hours then allowed to warm to room temperature and stirred for a further 20 hours. Methanol was added then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (×3) and brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2), eluting with 50% ethyl acetate/petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373. *This starting material can be made by the method described in J. Chem. Soc., Perkin Trans 1, 2000, p3444-3450
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C(Cl)Cl.C(O[Rh]OC(=O)C)(=O)C>[O:6]=[C:5]1[CH2:10][CH2:11][C:2]2([C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:1]2)[CH2:3][CH2:4]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC(=O)O[Rh]OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC12CCC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of diacetoxyrhodium (0.14 g, 0.317 mmol) and 8-methylene-1,4-dioxaspiro[4.5]decane (1.5 g, 9.73 mmol) in DCM (20 mL) was heated to reflux, and a solution of ethyl 2-diazoacetate (2.018 mL, 19.45 mmol) in DCM (6 mL) was added to it via syringe pump at 3.0 mL/h. The reaction mixture was stirred for 2 h after the completion of the addition, cooled to rt and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford ethyl (1S)-6-oxospiro[2.5]octane-1-carboxylate (1.9 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.08-4.18 (2H, m), 3.94-3.99 (4H, m), 1.83 (4H, m), 1.59-1.67 (2H, m), 1.49-1.58 (2H, m), 1.35-1.46 (1H, m), 1.23-1.30 (3H, m), 1.15 (1H, t, J=4.89 Hz), 0.90 (1H, dd, J=7.91, 4.39 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25]S(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:33][CH:34](O)[CH3:35]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:34]([CH3:35])[CH3:33])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Product: CCOC(=O)c1c(OC(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C) and propan-2-ol. Off white solid. LC-MS (ESI): 418 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ncc(N)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.4 %

Procedure:
10% Pd/C (1 g) was added to a solution of tert-butyl(2-methoxy-5-nitropyridin-3-yl)methylcarbamate (9.8 g, 34.6 mmol) in MeOH (150 mL) and DCM (75 mL) and the mixture stirred at rt for 7 h under an atmosphere of H2. The reaction mixture was then filtered through celite and washed with MeOH and the filtrate concentrated in vacuo. Purification by flash column chromatography eluting with 2:1 to 1:1 heptane-EtOAc yielded the title compound (7.4 g, 29.2 mmol) as a tan solid.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]([OH:18])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Cc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to tetrahydrofuran (2 ml) solution of 2-bromo-5-methylpyridine (510 mg, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise 2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling and then, the temperature of the reaction mixture was raised to room temperature gradually. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and then, the mixture was extracted with ethyl acetate. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (130 mg, 18%) as an oil.