Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(CCl)cc2o1
Reactant: Brc1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a stirred solution of 6-bromo-3H-imidazo[4,5-b]pyridine (506 mg, 2.55 mmol) from Step 1 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt, then stirred for a further 15 h. To the reaction mixture was added water and the mixture was extracted with EtOAc. The organic layer was separated and the aq layer extracted with additional EtOAc. The combined organic layers were washed with water then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (460 mg, 48%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.40 (d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 and 377 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:20][CH2:21][CH2:22]I>C1COCC1>[F:20][CH2:21][CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Temperature: 85 °C

Procedure:
In a sealed tube, 1,1-dimethylethyl 1-piperazinecarboxylate (10.0 g, 54.0 mmol) was dissolved in 100 mL of THF. K2CO3 (11.2 g, 81.0 mmol) and 1-fluoro-2-iodoethane (11.3 g, 64.8 mmol) were added and the reaction was heated to 85° C. for 16 h. The reaction was cooled to rt and solids were filtered and washed with DCM. The filtrate was concentrated in vacuo being careful not to heat the H2O bath past 30° C. The resulting crude product, 1,1-dimethylethyl 4-(2-fluoroethyl)-1-piperazinecarboxylate was carried on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.48 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 3.24-3.28 (m, 4H), 2.57 (dt, JHF=28.7, J=4.9 Hz, 2H), 2.31-2.36 (m, 4H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].Cl.I[CH2:42][CH2:43][O:44][CH2:45][CH2:46]I.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([N:38]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C@@H:3]1[OH:39]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: ICCOCCI
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N2CCOCC2)[C@H](O)[C@H](C)O1
Reaction time: 36 h
Yield: 62.3 %

Procedure:
To a solution of adriamycin hydrochloride (20 mg; 0.034 mmoles) in 1 ml of DMF were added 200 mg (0.614 mmoles) of bis(2-iodoethyl)ether and 0.014 ml (0.104 mmoles) of triethylamine, and the reaction was carried out for 36 hours at room temperature. The product was worked up in the same way as in the purification procedure of Example 1 to give 13 mg (yield 61%) of the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])/[CH:27]=[CH:28]/[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CSC>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:42])[CH2:27][C@H:28]([C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([C@@H](CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccccn2)c1
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a 1.0 M solution of isopropylmagnesium chloride (1.0 mL, 2.08 mmol) in THF was added 2-bromopyridine (0.198 mL, 2.08 mmol) and the mixture was stirred for 1.5 hours. This dark solution, at 0° C., was quickly added to a cooled (−40° C.) solution of CuBr.DMS complex (0.206 g, 1.01 mmol) in THF (2 mL) and dimethylsulfide (1 mL), and the resulting mixture was stirred at −40° C. for 10 min, then placed in an ice bath. Tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate from the previous step, dissolved in THF (2 mL), was added dropwise and the mixture was stirred for 1.5 hours. The reaction was quenched with 20% aqueous NH4Cl solution, the dimethylsulfide was removed under reduced pressure and the mixture was partitioned between EtOAc and H2O. The layers were separated, the water layer was extracted with EtOAc, and the combined organics were washed with H2O and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 10 g ISCO column using 0-40% EtOAc/hexanes over 40 min. The lower diastereomer was combined to give tert-butyl 3-{(1R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxo-1-pyridin-2-ylpropyl}benzoate as an oil (0.12 g, 37%). Absolute chirality was assigned based on literature precedent. TLC Rf=0.3 (1:1 EtOAc:hexanes, UV visualization); HPLC RT=2.1 min, method B; M+H=488.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][N:28]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][N:28]=3)[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: O=C(Nc1ccccc1)c1ccnc(Br)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3ccccc3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-phenyl-isonicotinamide were converted to the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][C:6]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:19]=[C:20]([C:23]3[NH:27][C:26]([C:28]#[N:29])=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:4]=2[NH:3]1.I[CH3:31]>>[CH3:31][N:27]1[C:23]([C:20]2[CH:21]=[CH:22][C:4]3[NH:3][C:2](=[O:1])[CH2:8][O:7][C:6]([C:14]4[S:15][CH:16]=[CH:17][CH:18]=4)([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)[C:5]=3[CH:19]=2)=[CH:24][CH:25]=[C:26]1[C:28]#[N:29]
Reactant: N#Cc1ccc(-c2ccc3c(c2)C(c2cccs2)(c2cccs2)OCC(=O)N3)[nH]1
Reactant: CI
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(c1cccs1)(c1cccs1)OCC(=O)N2

Procedure:
Prepared from 5-(2-oxo-5,5-dithien-2-yl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile and iodomethane generally according to the procedure of example 3. 1H-NMR (DMSO-d6) δ 10.33 (s, 1H), 7.63 (dd, J=5.0, 1.1 Hz, 2H), 7.50 (dd, J=8.3, 2.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.03 (m, 4H), 6.89 (dd, J=3.6, 1.1 Hz, 2H), 6.18 (d, J=4.0 Hz, 1H), 4.25 (s, 2H), 3.49 (s, 3H); MS (ES) m/z 432 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[C:21]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:20]1>CO>[CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:20][C:21]2([OH:19])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Reactant: C1CC2(CCO1)CO2
Solvent: CO
Product: O=C(NCC1CCN(CC2(O)CCOCC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.4 %

Procedure:
A mixture of benzyl(piperidin-4-ylmethyl)carbamate (7.77 g, 31.3 mmol, prepared according to Bose, D. Subhas et al., Tetrahedron Lett., 1990, 31, 6903) and 1,6-dioxaspiro[2.5]octane (4.29 g, 37.6 mmol, prepared according to Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) in methanol (93 mL) was stirred at room temperature for 20 h. Then, the mixture was refluxed for 8 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 5.60 g (49%) of the title compound as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCCCC(=O)O
Product: O=C(O)CCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 97.4 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 5-aminopentanoic acid (0.152 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.37 g (98%) 143 as dull white crystals: mp=172° C.; Rf 0.93 (A): Rf 0.83 (B): Rf 0.69 (D): 1H NMR (DMSO-d6) δ 1.83 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 3.64 (t, J=6.7 Hz, 2H), 8.01 (d, J=7.6 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H), 8.59 (dd, J=7.6, 1.9 Hz, 1H); IR (cm−1): 2750–3200 (OH), 3056 (C═CH), 2620 (C—H), 1773 (C═O), 1707 (bs, C═O), 1624 (C═C), 1543 (N═O), 1438 (C═C), 1403 (C—O), 1351 (N═O), 1217 (C—O), 1068 (C—O), 723 (C═CH); MS m/z (rel intensity) 305 (100).
Reaction SMILES: [CH:1](/[N:6]=[C:7]=[O:8])=[CH:2]\[CH:3]=[CH:4]\[CH3:5].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1](/[NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])=[CH:2]\[CH:3]=[CH:4]\[CH3:5]
Reactant: C/C=C/C=C/N=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C/C=C/C=C/NC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of trans,trans-1,3-pentadienyl isocyanate was added a solution of 5-fluorouracil (2.6 g.) in N,N-dimethylacetamide (15 ml.) at 80° C. and stirred for 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (100 ml.), washed with water (4 times), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 1-[N-(trans,trans-1,3-pentadienyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1[NH2:19])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCCl>[NH2:19][C:14]1[C:15](=[O:18])[C:16](=[O:17])[C:13]=1[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCNCc1c(N)c(=O)c1=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCCl
Product: Nc1c(CNCCP(=O)(O)O)c(=O)c1=O
Yield: 57.6 %

Procedure:
A suspension of [2-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)methylamino]ethyl]phosphonic acid diethyl ester (600 mg, 2.3 mmol) in anhydrous 1,2-dichloroethane (20 mL) under nitrogen was treated with bromotrimethylsilane (2.0 mL, 15 mmol) and heated to reflux for 10 minutes. The yellow solution was concentrated and the resulting solid was dissolved in water (75 mL), washed with diethyl ether (2×50 mL) and evaporated. The solid was dissolved in boiling methanol, filtered, and concentrated with the addition of ethyl acetate to a final volume of 75 mL to afford the title compound as a yellow solid (310 mg, 58%, mp 230°-260° C. dec); IR (KBr, cm-1): 3340, 1800; MS (-FAB): 233 (M-H, 32), 148 (100); 1H NMR (DMSO, 400 MHz): δ 7.62 (br s, NH2), 3.68 (br s, 2H), 3.16 (br s, 3 H), 1.90 (d of t,J=18 and 7.5 Hz, 2H).
Reaction SMILES: [CH:1]([N:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5](=[O:30])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH:16]=O)[C:11](=[O:19])[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]1=2)([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:1]([N:4]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:5](=[O:30])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:11](=[O:19])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]1=2)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC=O)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CCNc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a stirred solution of 135 mg (0.28 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-3-(2-oxoethyl)-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Intermediate 9, and 130 mg (1.40 mmol, 5.0 equiv) of aniline in 5 mL of methanol is added 18 mg (0.28 mmol, 1.0 equiv) of NaBH3CN and 1 drop of glacial acetic acid. The resulting mixture is stirred 30 min at RT, then quenched by the addition of 0.1 mL H2O and the solvent removed in vacuo. The residue is then dissolved in 40 mL of EtOAc and extracted with 0.5N HCl (1×40 mL); the organics are dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification by reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization to afford 120 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz, mixture of conformational isomers) δ7.54-6.73 (m, 19H), 5.04 (m, 1H), 4.54 (d, 0.5H, J=16.6), 4.24 (m, 2H), 3.80 (d, 0.5H, J=16.6), 3.62 (m,1H), 3.34 (m, 0.5H), 2.40 (s, br, 1H), 2.05 (m, 0.5H), 1.80 (m, 0.5H), 1.62 (s, 1H), 1.12 (m, 6H); low resolution MS (FAB)m/e 561 (MH+), 468.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][N:25](C)C=O>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)#[N:25]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C#N)ccc1-2
Yield: 71.3 %

Procedure:
8-Bromo-2-isopropyl-2H-1,2,4-triazol-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (330 mg, 0.84 mmol) and degassed dimethylformamide (4.2 mL) were added to a CEM microwave vial. The mixture was thoroughly purged with nitrogen. Zinc cyanide (99.0 mg, 0.84 mmol, 1.0 equiv.) and Pd(PPh3)4 (48.7 mg, 0.04 mmol, 0.05 equiv.) were added to the reaction mixture in one portion and the vial was sealed immediately. The reaction was submitted to MW irradiation at 60 W for 15 minutes (T=175° C.). The mixture was diluted with methylene chloride, filtered through celite, and washed with saturated NH4Cl. The organic layers were combined, dried with MgSO4 and concentrated. The crude mixture was loaded onto silica gel and purified by flash chromatography (0-100% EtOAc in hexanes) to give 202 mg (71.3% yield) of 8-cyano-2-isopropyl-2H-1,2,4-triazol-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene a yellow solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C@@H:13]([O:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)(C(C)(C)C)(C)C.Cl.C(O)(C)C>CO>[OH:8][C@@H:9]1[CH2:14][C@@H:13]([O:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1
Reactant: CO[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CO[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-methoxypiperidine-1-carboxylate (1 eq) in 30 mL of methanol was added 3.8M HCl in isopropanol (4 eq). The reaction mixture was allowed to stand at room temperature for 3 hours at which point it was concentrated under reduced pressure. The resulting residue was diluted with 100 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=2:1) to yield (3R,5R)-benzyl 3-hydroxy-5-methoxypiperidine-1-carboxylate (92%). LC/MS (m/z): 266.2 (MH+).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:33]([CH:35]([CH2:40][C:41]1[CH:42]=[N:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=1)[C:36](OC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([F:24])[C:9]=1[O:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16][CH:15]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:36]=[C:35]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=2)[C:33](=[O:34])[N:25]=1
Reactant: N=C(N)OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)cn1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
To the solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (200 mg, 0.421 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (113 mg, 0.505 mmol) in 1,4-dioxane (2 mL) was added K2CO3 (233 mg, 1.683 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (65 mg, 28.8% yield). LCMS: rt=3.05 min, [M+H+]=537
Reaction SMILES: C1(C([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]=2[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=O)C=CC=CC=1.O1CCCC1>CO.[OH-].[Na+]>[C:26]1([C:24]([C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[CH:15][C:10]=2[NH2:9])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1
Yield: 107.1 %

Procedure:
A solution of phenyl-N-[2-(phenylcarbonyl)-4-(phenylmethoxy)phenyl]carboxamide (3.24 g, 8.0 mmol) in methanol (20 mL) and 10 N sodium hydroxide (NaOH) (6 mL) was heated to reflux temperature when tetrahydrofuran (THF) (15 mL) was added. The solution was then heated to reflux overnight when the methanol and THF was removed under vacuo. The solution was then added to water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuo to an oil to isolate the title compound (2.60 g, >100% yield, analytical).
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([N:13]2[CH:7]=[N:8][C:9]([NH2:12])=[N:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1noc(-c2ccccc2)n1
Reactant: Nc1ccccc1
Product: Nc1ncn(-c2ccccc2)n1
Yield: 87 %

Procedure:
This compound was prepared from 5-phenyl-[1,2,4]oxadiazol-3-ylamine (Journal of Organic Chemistry 28, 1812 (1963) and aniline, via the rearrangement described by Ruccia et al., Journal of Heterocyclic Chemistry 8, 137 (1971). The title compound was isolated as a slightly brownish solid in a yield of 87%. MS ISP (m/e): 161.2 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].C(O)(=O)C.[CH3:20][C:21]([CH3:23])=O>>[C:1]([O:5][C:6]([NH:7][N:8]=[C:21]([CH3:23])[CH3:20])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Product: CC(C)=NNC(=O)OC(C)(C)C

Procedure:
To a solution of tert-butylcarbazate (50.0 g, 378 mmol) in 40 mL acetone is added 10 g MgSO4 and 5 mL acetic acid and the reaction mixture is stirred at reflux temperature for 1 h. The reaction mixture is filtered and concentrated in vacuo. The residue is crystallized from diethyl ether/cyclohexane. Yield: 49.4 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:16]Cl.[BH4-].[Na+]>CO>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:16][N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1
Reactant: c1cnc2ccncc2c1
Reactant: COc1ccc(CCl)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN2CCc3ncccc3C2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (5.2 g, 0.04 mol) and 3,4-dimethoxybenzyl chloride (8.95 g, 0.048 mol) was refluxed for 3 hours. The precipitated quatenary salt was separated by filtration, dissolved in technical grade methanol (400 ml) and sodium borohydride (15.1 g, 0.4 mol) was added portionwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by alumina column chromatography (eluted successively with n-hexane, benzene and chloroform). The resulting residue was recrystallized from ether-n-hexane to afford the Compound No. 46 (6.5 g, 57.2%) as colorless prisms, mp. 76°-77° C.