Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][C:17]=1[CH:18]=O.C[O-].[Li+]>CN(C)C=O.O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][C:17]=1/[CH:18]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 60 %

Procedure:
Ex-48A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.13 g, 0.64 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 0.15 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added lithium methoxide (1.0 M in methanol, 1.6 mL, 1.6 mmol). The solution was allowed to stir at ambient temperature for 13 h and then at 40° C. for 2 h. HPLC indicated no further change of starting materials. The reaction mixture was then diluted with water, acidified to pH 5. The resulting precipitate was collected by filtration, washed with water, dried in vacuo. The crude product was slurried in ethanol overnight. The solid was collected by filtration, washed with ethanol, dried in vacuo to give 4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide (0.16 g, 59%) as a red solid, m.p. 220–222° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=8.7 Hz, 2H), 8.04 (d, J=16.1 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.64 (d, J=16.1 Hz, 1H), 7.52 (s, 2H), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.19–3.17 (m, 4H), 1.84–1.83 (m, 4H). HRMS Calcd for C21H24N2O5S: 416.1408 (M+); Found: 416.1408.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:23]2[S:27][C:26]([C:28]3([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)[CH:9]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:11]=1.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[OH:34][C:28]1([C:26]2[S:27][C:23]([C:8]3[CH:9]=[C:10]([NH:12][C:13]4[N:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][N:14]=4)[CH:11]=[C:6]([CH3:5])[CH:7]=3)=[CH:24][N:25]=2)[CH2:29][CH2:30][N:31]([C:1](=[O:3])[CH3:2])[CH2:32][CH2:33]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1

Procedure:
To a mixture of acetic acid (9 μL, 0.15 mmol) and Si-carbonyl diimidazole (266 mg, 0.287 mmol) was added a solution of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) and hydroxybenzotriazole (26 mg, 0.17 mmol) dissolved in N,N-dimethylformamide, and the resultant suspension was shaken in a Bohdan block overnight at room temperature. The reaction mixture was filtered and concentrated in vacuo, and the resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 1-{4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone. MS ESI: [M+H]+ m/z 478.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.95 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 1H), 4.25-3.99 (m, 1H), 3.73 (m, 1H), 3.41-3.34 (m, 1H), 3.07-2.97 (m, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 2.25-2.14 (m, 1H), 1.93 (m, 2H), 1.75 (m, 1H). rhSYK activity=+++
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[N:27][CH:26]=1)[CH:20]([NH:36][C:37](=[O:67])[C:38](=[N:64][O:65][CH3:66])[C:39]1[N:40]=[C:41]([NH:44]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:42][CH:43]=1)[C:19]2=[O:68])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)=O>[NH2:44][C:41]1[S:42][CH:43]=[C:39]([C:38](=[N:64][O:65][CH3:66])[C:37]([NH:36][CH:20]2[C:19](=[O:68])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([C:25]2[S:29][C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[N:27][CH:26]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:67])[N:40]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4cccnc4)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: COc1ccccc1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4cccnc4)s3)CSC12)c1csc(N)n1
Yield: 89.2 %

Procedure:
The syn isomer of 2-benzhydryloxycarbonyl-7[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.1 g) is treated with formic acid (20 cc) containing anisole (2 cc) for 30 minutes at 50° C. and the reaction mixture is then concentrated to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. The residue is taken up in ethanol (20 cc), which is evaporated off under reduced pressure (30 mm Hg; 4 kPa) at 40° C.; this operation is repeated a further 2 times. The residue is solidified with ethanol (150 cc). The solid is filtered off, washed with ethanol (2×5 cc) and ethyl ether (3×20 cc) and dried to give the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-8-oxo-3-[2-(pyridin-3-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.56 g) in the form of a pale yellow solid.
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.C(OCC)(=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>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:1]=[CH:2]/[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:10][N:11]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[CH:16][CH:15]=2)=[CH:32][N:31]=1
Reactant: COc1ccc(Br)cn1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40 %

Procedure:
6-(22-methoxypyridin-5-yl)-3-(((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole was converted to 6-(2-methoxypyridin-5-yl)-3-E-styryl-1H-indazole in a similar manner to that described for Example 27(a). 1H NMR (300 MHz, CDCl3) □8.53 (d, 1H, J=2.1 Hz), 8.15 (d, 1H, J-9.2 Hz), 7.97 (dd, 1H, 1=2.6, 8.6 Hz), 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, J=8.6 Hz). HRMS (FAB) [M+H]/z Calc'd 328.1450, found 328.1462. Anal. Calc'd, C (77.04), H (5.23), N (12.83). Found: C (77.00), H (5.28), N (12.65). The starting material was prepared as follows: A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanylthoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150 ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, 1=8.3 Hz), −0.03 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(C)cc1)CCNCC2
Yield: 109.5 %

Procedure:
The title compound (136 mg) was prepared as in Example 177, Steps C and D, using 201 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 198 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3, 255.17; found, m/z 256.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.67 (br s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.92-3.41 (m, 2H), 3.28-3.18 (m, 3H), 2.89-2.80 (m, 2H), 2.43 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[C:12]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>C(O)C>[Cl:25][C:26]1[O:30][C:29]([CH:31]2[C:5]3=[C:6]4[N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10](=[O:19])[C:11]4=[C:12]([C:13]4[S:14][CH:15]=[C:16]([CH3:18])[N:17]=4)[N:4]3[CH2:3][CH:2]([CH2:23][OH:24])[O:1]2)=[CH:28][CH:27]=1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(O)CO)n1
Reactant: O=Cc1ccc(Cl)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CO)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 6-(2,3-dihydroxypropyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (450 mg, 1.284 mmol), 5-chlorofuran-2-carbaldehyde (184 mg, 1.413 mmol) and bismuth triflate (169 mg, 0.257 mmol) in ethanol (9.584 ml) was stirred at room temperature for 2.5 hours. TFA (310 μl) was added and the mixture heated under microwave radiation at 80° C. for 20 mins, then further heated under microwave radiation at 80° C. for 10 hours. The reaction was then concentrated to half-volume under vacuum, a further portion of bismuth triflate (169 mg, 0.257 mmol) and powdered molecular sieves (200 mg) were added and the mixture heated under microwave radiation at 80° C. for 10 hours. The mixture was evaporated under vacuum and the residue partitioned between EtOAc (100 ml) and saturated K2CO3(aq) (100 ml) The phases were separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-50% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:65]([O:69][C:70](=[O:77])[NH:71][CH2:72][CH:73]([OH:76])[CH2:74][NH2:75])([CH3:68])([CH3:67])[CH3:66]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@H:45]([CH2:46][C:47]([NH:75][CH2:74][CH:73]([OH:76])[CH2:72][NH:71][C:70]([O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:77])=[O:49])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
418.2 mg (1.1 mmol) of HATU and 258.7 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 428.5 mg (1 mmol) of (3S)-3,7-bis{[(benzyloxy)carbonyl]amino}heptanoic acid in 30 ml of anhydrous DMF. After stirring at RT for 15 min, 209.2 mg (1.1 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.ClC1SC(S(N(S(C2SC(Cl)=CC=2)(=O)=O)C2C3C(=CC=CC=3OC)N(C(OC(C)(C)C)=O)N=2)(=O)=O)=CC=1.Cl[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([O:62][CH3:63])[CH:55]=1>CS(C)=O.O>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([CH2:53][N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([NH2:14])=[N:8]2)[CH:59]=[CH:58][C:57]=1[O:60][CH3:61]
Reactant: COc1ccc(CCl)cc1OC
Reactant: COc1cccc2[nH]nc(N)c12
Agent: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1OC
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Powdered KOH (0.494 g, 8.80 mmol) was dissolved in DMSO (20 mL) under nitrogen and 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.653 g, 4 mmol) was added. The mixture was stirred for 15 min to give a deep red solution. 4-(Chloromethyl)-1,2-bis(methyloxy)benzene (0.896 g, 4.80 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was added to water (150 mL) and extracted with dichloromethane (3×50 mL). The dried (Na2SO4) extract was evaporated and the residue was triturated with diethyl ether (3×3 mL) to give the title compound (1.05 g, 84%) as an orange solid. LCMS (System B) RT=1.42 min, ES+ve m/z 314 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([O:17]C)=O)=[C:4]([F:21])[CH:3]=1.[Si:22]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][NH2:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([NH:33][O:32][CH2:31][C@@H:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23])[CH3:34])=[O:17])=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Reactant: C[C@@H](CON)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.050 g, 0.14 mmol) and (S)-O-(2-(tert-butyldimethylsilyloxy)propyl) hydroxylamine (0.072 g, 0.35 mmol) in THF (1.50 mL) at 0° C. was slowly added lithium bis(trimethylsilyl)amide (0.70 ml, 0.70 mmol). After addition, the reaction mixture was stirred for 1 hour at room temperature and then quenched by with saturated NaHCO3. The reaction mixture was partitioned between EtOAc and sat NaCl. The layers were separated and the aqueous layer was back-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude brown solid that was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=1.C(N(CC)CC)C>CCO>[Cl:9][C:10]1[N:11]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:13]=[C:14]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH:15]=1
Reactant: CC1(C)CNCCO1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)CN(c2cc(Cl)nc(N3CCOCC3)n2)CCO1
Temperature: 110 °C

Procedure:
A mixture of 2,2-dimethylmorpholine (2.0 equiv.), 4-(4,6-dichloropyrimidin-2-yl)morpholine (1 equiv.) and triethylamine (6 equiv.) in EtOH (0.2 M) were heated to 110° C. for 25 min in the microwave. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate. The resulting solution was concentrated and dried under vacuo to give 4-(6-chloro-2-morpholinopyrimidin-4-yl)-2,2-dimethylmorpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=313.2, Rt=0.86 min.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].[CH2:12](O)[CH3:13].C(Cl)(=O)C>C1C=CC=CC=1>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)c1cc(C(=O)O)[nH]n1
Solvent: c1ccccc1
Solvent: CC(=O)Cl
Product: CCOC(=O)c1cc(C(C)C)n[nH]1

Procedure:
To a clean round bottom flask equipped with a stir bar, Dean-Stark trap, and reflux condenser was added 3-isopropyl-1H-pyrazole-5-carboxylic acid (1 gram, 6.49 mmol, purchased from Fisher Scientific). 30 mL of ethanol (95%, purchased from Fisher Scientific) was added followed by 30 mL of benzene. 43 μL of acetyl chloride was then added and the solution refluxed over the three days. The solvent was then removed using a Buchi rotoevaporator. The residue was then taken up in ethyl acetate and washed with NaHCO3 (saturated). It was then dried with sodium sulfate, filtered and concentrated. Purification using a Teledyne ISCO silica chromatography (hexanes/ethyl acetate gradient) afforded the desired ester. Yield, 85% 1H-NMR δ 6.7 (s, 1H), 5.1 (bs, NH), 4.41 (q, 2H), 3.13 (septet, 1H), 1.38 (t, 3H), 1.33 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:15][CH:16]=C)[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].C(OCC)(=[O:20])C>CC(O)C.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:15][CH:16]=[O:20])[CH2:6][CH2:7][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: C=CCC1(C(=O)OC)CCC(C(=O)OC)CC1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1CCC(CC=O)(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
1-Allyl-cyclohexane-1,4-dicarboxylic acid dimethyl ester (4.50 g, 17.71 mmol) was dissolved in 2-propanol (100.0 mL) and water (50.0 mL). To this was added an aqueous solution of NaIO4 (9.50 g, 44.3 mmol) in water (50.0 mL), followed by addition of OsO4 (0.025 g, crystals, in one portion). The reaction mixture was allowed to stir for 16 hours. Then, the reaction mixture was poured into ice water (50 mL) and ethyl acetate (EtOAc) (60 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic solutions were washed with brine, and concentrated to dryness. The material was then purified over silica gel column eluting with ethyl acetate in heptanes (0-60%) to afford 3.09 g (72%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([NH:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1nc(Cl)ccc1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 6-chloro-2,3-diaminopyridine (2.00 g, 13.9 mmol, Combi-Blocks) and benzaldehyde (1.48 g, 13.9 mmol, Aldrich) in 1,2-dichloroethane (50 mL) was treated with acetic acid (0.2 mL, 3 mmol) and the mixture was allowed to stir for 30 minutes. Na(OAc)3BH (8.8 g, 42 mmol) was added and the reaction was stirred overnight. The reaction was quenched with water, then poured into saturated NaHCO3 solution. The product was extracted with three portions of DCM, and the combined extracts were washed with saturated NaHCO3 solution and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-75% EtOAc in hexanes was used to afford purified product.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=1)[CH3:14].[CH3:23][C:24]12[CH2:31][CH:28]([NH:29][CH2:30]1)[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2.O>C(Cl)Cl>[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([N:29]2[CH2:30][C:24]3([CH3:23])[CH2:31][CH:28]2[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]3)=[O:22])[CH:16]=1)[CH3:14]
Reactant: CCc1cc(C(=O)O)cs1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.06 g; 1.2 eq) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid (0.04 g; 1 eq.) in DCM (1 mL/100 mg of starting material). This mixture was stirred at room temperature for 5 minutes, then 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.043 g; 1.1 eq.) added and the mixture allowed to stir for 18 hours. Water (1 mL/100 mg of starting material) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane) to give the title compound (0.046 g). LCMS m/z 292 [M+H]+ RT=4.28 min (Analytical Method 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[F-].[Cs+]>C(#N)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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 81.7 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (3.70 g, 24.3 mmol), 1-chloro-4-nitrobenzene (3.84 g, 24.3 mmol) and cesium fluoride (7.40 g, 48.7 mmol) in 150 mL of 2:1 acetonitrile-water was degassed under vacuum for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (844.0 mg, 0.73 mmol) was added and the reaction refluxed for 3 h. The solvent was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic phase was separated, dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue on silica gel using 5% ethyl acetate hexanes as the eluent gave 4′-methoxy-4-nitro-biphenyl (4.55 g, 81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:12][CH3:13])[C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][O:12][CH3:13])=[N:3][CH:4]=1
Reactant: C#CCOC
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
2,5-Dibromopyridine (16-582 g) was dissolved in triethylamine (200 ml), followed by the addition of methyl propargyl ether (5.9 ml), copper iodide (267 mg) and bis(triphenylphosphine)palladium (II) chloride (46 mg). The resulting mixture was stirred in nitrogen atmosphere at room temperature for 1 hr. Subsequently, it was stirred at room temperature for further 3 hr. After the resulting insoluble matters were filtered off, the resulting solution was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a brown solid (12.411 g, yield; 79%).