Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[S:12])([O-:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[N:13][C:14](=[O:16])[CH3:15])[S:12][CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)NC(=S)Nc1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(C)=O)Nc1ccccc1[N+](=O)[O-]
Yield: 42 %

Procedure:
6.5 g (0.026 M) of N-(o-nitrophenyl)-N'-acetyl-thiourea, 2.1 g (0.015 M) of potassium carbonate, 1.9 ml (0°-0.29 M) of methyl iodide and 70 ml of acetone are boiled in a reflux for four hours. The acetone is distilled off. Water is added to the residue and it is filtered. After drying 6.6 g (100% of the theoretical yield) of the product are obtained with a melting point of 118°-160°. After recrystallization twice from ethanol and isopropanol N-(o-nitrophenyl)-N'-acetyl-S-methylisothiourea with a melting point of 120°-122° C. and 42% yield of the theoretical one is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[C:31]([O:35][C:36]([N:38]1[C@H:43]([CH2:44][NH2:45])[CH2:42][C@@H:41]2[C@H:39]1[CH2:40]2)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[C@H:43]([CH2:44][NH:45][C:11]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:9])=[O:13])[CH2:42][C@@H:41]2[C@H:39]1[CH2:40]2)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@H]2C[C@H]21
Reactant: Oc1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)Oc2cccc(Cl)c2F)C[C@H]2C[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-2-fluorophenol (180 mg, 1.20 mmol) in dry CH2Cl2 (10 mL), cooled to at 0° C., was added triphosgene (120 mg, 0.4 mmol) followed by dropwise addition of a solution of DIPEA (210 μL, 1.20 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to RT and stirring was continued for 1 h. The reaction mixture was then added dropwise to a solution of (1R,3S,5R)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (170 mg, 0.80 mmol) (prepared as described in Part B) and DIPEA (168 μL, 0.96 mmol) in CH2Cl2 (10 mL) at RT. After stirring for 2 h, the reaction was quenched by addition of methanol (2 mL) and water with vigorous stirring. The mixture was extracted with CH2Cl2 (2×), the combined organics were washed with brine, dried (phase separator) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 9:1 to c-hexane/EtOAc 1:1) afforded the title compound as a colorless wax. MS (LC/MS): 385.0 [M+H]+; tR (HPLC conditions k): 4.03 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:16](=[NH:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][C@H:10]1[NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:29]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:7]=2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ccnc(Cl)c2)C[C@H](C)N1
Reactant: N=C(c1ccccc1)c1ccccc1
Product: C[C@@H]1CN(c2ccnc(N=C(c3ccccc3)c3ccccc3)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a similar manner to cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine (D19) using cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine (D19) and benzophenone imine as the starting materials. MS (ES+) m/e 371 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+].BrCCCCC[C:34]1[CH:44]=[CH:43][CH:42]=[C:36]2[C:37]([NH:39][C:40](=[O:41])[C:35]=12)=O>CN(C)C=O>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:18][CH2:3][CH2:4][CH2:5][CH2:37][N:39]3[C:40](=[O:41])[C:35]4[C:34](=[CH:44][CH:43]=[CH:42][CH:36]=4)[C:22]3=[O:25])[CH2:15][CH2:16]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C1NC(=O)c2c(CCCCCBr)cccc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 113.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide hydrochloride (23.0 g) was dissolved in dimethylformamide (250 ml). Potassium carbonate (28.5 g) and 5-bromopentylphthalimide (20.4 g) were added, and the mixture was stirred at 50° C. for 8 hr. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 20.0 g of 4-amino-5-chloro-N-(1-(5-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)pentyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])=[C:18]([F:23])[CH:17]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F

Procedure:
To 3.5 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 100 mL of absolute ethanol was added 2.3 mL of 4-chloro-2-fluoroaniline. After stirring the reaction under an inert atmosphere for 24 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ethyl acetate/hexanes. Drying in vacuo yielded 1.9 (40%) of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 249-252° C.; mass spectrum (m/e): M+H 316.9.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)Cl.[Si]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[NH:28][CH:27]=[CH:26]2)(C(C)(C)C)(C)C.[CH3:30][O-:31].[Na+].CO>CCOCC>[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[NH:28][CH:27]=[C:26]2[C:1](=[O:5])[C:2]([O:31][CH3:30])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccc2cc[nH]c12
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(CCCO)cccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A 2.0 M solution of oxalyl chloride in methylene chloride (9.30 mL, 18.6 mmol) was added to a solution of 7-[3-(tert-butyldimethylsilyloxy)propyl]-1H-indole (4.9 g, 16.9 mmol) in ether (40 mL) dropwise over 15 min at 4° C. under N2. The ice bath was removed and the resulting mixture was stirred for 1.5 h. A 25% sodium methoxide in methanol solution (8.1 mL, 32.4 mmol) was added at −78° C. over 5 min. The mixture was allowed to warm up to room temperature and stirred for 2 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with saturated NH4Cl (60 mL), saturated NaCl (60 mL), dried (MgSO4) and concentrated to a red solid. Flash chromatography (SiO2, 50% EtOAc/CH2Cl2) gave the title compound (4.3 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 12.44 (s, 1H), 8.43 (d, J=3 Hz, 1H), 8.04 (d, J=8 Hz, 1H), 7.24 (dd, J=8, 8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 3.94 (s, 3H), 3.50 (t, J=6 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H), 1.78 (m, 2H). MS (electrospray, m/z) 260.1 (M−−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.O>CN(C)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>[ClH:1].[CH3:20][C:19]1[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=[CH:16][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([C:38]3[CH:39]=[CH:40][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Reactant: OCc1ccc(B(O)O)cc1
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: O
Solvent: CC(=O)N(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CO)cc3)CC2)cnn1-c1ccccc1
Product: Cl
Yield: 52.8 %

Procedure:
Combine 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.290 g, 0.786 mmol), potassium carbonate (0.261 g, 1.89 mmol), 4-(hydroxymethyl)phenylboronic acid (0.143 g, 0.943 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) in N,N-dimethylacetamide (1.6 mL). Add water (790 μL), and reflux reaction for 18 hr. Add 4-(hydroxymethyl)phenylboronic acid (0.072 g, 0.471 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.009 g, 0.008 mmol) and heat to 110° C. for 3.5 hr. Add DCM and wash with water. Extract water layer three times with DCM. Dry combined organics (magnesium sulfate) and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 methanol:ethyl acetate), to give the free base of the title compound (198 mg, 57%). Dissolve the free base (0.195 g, 0.443 mmol) in acetonitrile (531 μL) and add aq. 1 N HCl solution (531 μL, 0.531 mmol). Shake for 15 min. at ambient temperature. Freeze dry to give the title compound (208 mg, 98%). MS (ES): m/z=441 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43](=[O:58])[NH:44][C@H:45]([C:51]3[CH:52]=[N:53][CH:54]=[C:55]([OH:57])[CH:56]=3)[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:38]2)=[O:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[F:59][C:60]1[CH:67]=[CH:66][C:65]([CH2:68]O)=[CH:64][C:61]=1[C:62]#[N:63].N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[C:62]([C:61]1[CH:64]=[C:65]([CH:66]=[CH:67][C:60]=1[F:59])[CH2:68][O:57][C:55]1[CH:56]=[C:51]([C@@H:45]([NH:44][C:43]([C@@H:39]2[CH2:40][CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][CH2:33][CH:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:26])[CH2:32][CH2:31]3)[CH2:38]2)=[O:58])[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:52]=[N:53][CH:54]=1)#[N:63]
Reactant: N#Cc1cc(CO)ccc1F
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(F)c(C#N)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 7.8 %

Procedure:
Polymer bound triphenylphosphine (30 mg) and tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 30 mg, 60 μmol) were stirred in dichloromethane for 30 minutes. 2-Fluoro-5-(hydroxymethyl)benzonitrile (26 mg, 0.17 mmol) in THF was added and the mixture was cooled to 0° C. Dipropan-2-yl diazene-1,2-dicarboxylate (20 μL, 0.11 mmol) was added, the mixture was stirred for 3 hours at room temperature and then stored for 16 hours at 5° C. After filtration the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 3.2 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:8]=2[C:7](=[O:14])[O:6]1)[CH:2]([CH3:4])[CH3:3].[CH:21](=[O:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>C1COCC1>[C:21]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:14])[O:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[CH2:10]1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C/C=C/c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)C=Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol) in THF (5 mL) was added trans-cinnamaldehyde (49 mg, 0.369 mmol) and the reaction mixture stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (117 mg, 0.553 mmol) was added and the reaction mixture stirred at room temperature for additional 2 hours. Ethyl acetate (10 mL) was added and the organic solution washed with sat. NaHCO3 (10 mL), brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (12 g, SiO2, 0 to 20% ethyl acetate in hexanes) to provide 5-cinnamoyl-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (45 mg, 63%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-1.05 (m, 6H), 1.54-1.84 (m, 2H), 2.20-2.48 (m, 3H), 2.52-2.66 (m, 1H), 2.73-2.89 (m, 1H), 2.99-3.14 (m, 1H), 3.19-3.37 (m, 2H), 3.43 (d, J=17.71 Hz, 1H), 6.23 (dt, J=15.82, 6.59 Hz, 1H), 6.44-6.57 (m, 1H), 7.20-7.46 (m, 10H); MS m/z 388 (M+H)+, 410 (M+23)+, 386 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Br:9]Br>C(O)(=O)C>[BrH:9].[Br:9][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1cccc(N)n1
Solvent: CC(=O)O
Product: Br
Product: Cc1nc(N)ccc1Br
Temperature: 35 °C
Reaction time: 1 h
Yield: 147.6 %

Procedure:
2-Amino-6-picoline (39.8 kg, 99.6 wgt % purity, 367 mol, 1.00 eq) was charged into acetic acid (65.0 kg) while the temperature rose to 60° C. Additional acetic acid (17 kg) was charged to wash in the last of the picoline and the mixture was heated to 35° C. until dissolution occurred. After cooling to 18° C., bromine (56.2 kg, 352 mol, 0.96 eq) was charged at 18±3° C. over 2 hours. More acetic acid (2.0 kg) was charged to wash in the last of the bromine. The mixture was held at this temperature range for 1 hour and then cooled to 11–15° C. It was held in this range for 0.5 hours. The solids were recovered by filtration on polypropylene and washed with isopropanol (63.0 kg) to produce 69.6 kg of moist 5-bromo-2-amino-6-picoline hydrobromide (76 wgt % of product as hydrobromide). This corresponds to a 54% yield. Part of this product was dried for the purposes of recording the 13C NMR spectrum: 13C NMR (400 MHz, DMSO-d6) δ 154.1, 146.9, 112.4, 105.2, 20.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]([CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][CH:46]2[C:51](O)=[O:52])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:33][NH:32][C:30](=[O:31])[CH2:29][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]1)=[O:52])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N(CC(=O)NN)C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(N(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
DIPEA (14 g, 0.11 mol) was added to a 0° C. solution of tert-butyl 3-(tert-butoxycarbonyl(2-hydrazinyl-2-oxoethyl)amino)azetidine-1-carboxylate (15 g, 0.044 mol), (5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (10 g, 0.036 mol) and HATU (15 g, 0.04 mol) in CH2Cl2 (250 mL). The mixture was allowed to warm to rt then was stirred at rt for 2 hrs. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0-50% EtOAc/petroleum ether) to afford tert-butyl 3-((2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)(tert-butoxycarbonyl)amino)azetidine-1-carboxylate (18.5 g, 86%). ESI-MS (EI+, m/z): 603.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:10]=C)=[CH:4][N:3]=1.[O:12]=[O+][O-].CSC>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH:10]=[O:12])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(Cl)nc1NC
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Solvent: ClC(Cl)Cl
Product: CNc1nc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 95 %

Procedure:
A solution of (2-chloro-5-vinyl-pyrimidin-4-yl)-methylamine (2.50 g, 14.7 mmol) in CHCl3/MeOH (15 mL/15 mL) is bubbled by ozone for 30 minutes and then passed by a stream of argon for 3 minutes at −78° C. The reaction mixture is allowed to warm up to room temperature and treated with dimethyl sulfide (3.24 mL, 44.1 mmol). The reaction mixture is concentrated under reduced pressure to give colorless oil that is purified by flash column chromatography (SiO2, EtOAc/Hx=1/3) over silica gel to give 2-chloro-4-methylamino-pyrimidine-5-carbaldehyde (2.40 g, 95%) as a white solid.
Reaction SMILES: N(O[CH2:4][CH2:5][CH2:6][CH3:7])=O.N[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11](O)=O.C1CC=CC=1>ClCCl.CC(C)=O>[N+:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:9]2[C:10]=1[CH:11]1[CH2:7][CH:6]2[CH:5]=[CH:4]1)([O-:20])=[O:19]
Reactant: CCCCON=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Agent: C1=CCC=C1
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1C1C=CC2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
In a three necked flask equipped with thermometer, dropping funnel and cooler with a bubbler, tertio-butyl nitrite (5.77 ml, 1.77 eq, 48.6 mmol) is dissolved in dichloromethane (30 ml) and heated to reflux while a solution of cold 2-amino-6-nitro-benzoic acid (5 g, 1 eq, 27.5 mmol) and cyclopentadiene (40.7 ml, 18 eq, 0.49 mol) in acetone (20 ml) is added dropwise. Care should be taken regarding gas evolution. After refluxing for 18 hours, the reaction is cooled down to ambient temperature before being filtrated through a silica pad and evaporated. The crude mixture is purified by chromatography column (silica gel, elution with a gradient from pure cyclohexane to a mixture of ethyl acetate:cyclohexane 1:12. 3 grams of 5-nitro-1,4-dihydro-1,4-methano-naphthalene are then obtained (58% yield). 1H NMR (CDCl3) 7.7 ppm, 1H, dd, J=0.7 and 8.4 Hz; 7.45 ppm, 1H, dt, J=7.3 and 0.7 Hz; 7.07 ppm, 1H, dd, J=7.3 and 8.4 Hz; 6.9-6.86 ppm, 2H, m; 4.86 ppm, 1H, bs; 4.02 ppm, 1H, bs; 2.38 ppm, 1H, dt, J=7.7 and 1.5 Hz; 2.3 ppm, 1H, dt, J=7.4 and 1.5 Hz.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.[NH:44]1[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH2:21][N:44]4[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]4)[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: OC[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CC[C@@H](CO)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.310 g, 0.537 mmol) and (R)-pyrrolidin-3-yl-methanol (0.163 mL, 1.610 mmol) in dichloromethane (0.035 mL, 0.537 mmol) and methanol (0.022 mL, 0.537 mmol) was treated with sodium triacetoxyborohydride (0.341 g, 1.610 mmol). The solution was stirred at room temperature overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 10% 2 M NH3.MeOH in CH2Cl2 to give (R)-(1-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)pyrrolidin-3-yl)methanol (0.188 g, 0.284 mmol, 52.9% yield). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[CH:24]=[C:23]([CH3:25])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]=1[N:26]1[C:30]([C:31]([F:34])([F:33])[F:32])=[N:29][N:28]=[C:27]1[SH:35].CN(C=O)C>C1COCC1.O>[CH3:14][C:15]1[CH:24]=[C:23]([CH3:25])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]=1[N:26]1[C:30]([C:31]([F:34])([F:33])[F:32])=[N:29][N:28]=[C:27]1[S:35][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)c(-n2c(S)nnc2C(F)(F)F)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1nnc(C(F)(F)F)n1-c1c(C)cc(C)c2c1CCCC2
Temperature: 60 °C
Yield: 54.2 %

Procedure:
Ethyl 2-bromoacetate (68 μL, 0.611 mmol) and potassium carbonate (0.17 g, 1.22 mmol) were added to a solution of 4-(2,4-Dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.611 mmol) in THF (2.44 mL). The resulting mixture was heated at 60° C. for 18 hours. The mixture was concentrated, ethyl 2-bromoacetate (68 μL, 0.611 mmol) and DMF (1.2 mL) added, and the mixture heated at 60° C. for 24 hours. Water (40 mL) was added and the mixture extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by SGC (0-50% ethyl acetate/Hexanes) to afford ethyl 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetate as a clear oil (0.137 g, 54%).