Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([Cl:47])[C:41]([CH2:45]Br)=[C:42]([Cl:44])[CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([CH2:45][C:41]1[C:40]([Cl:47])=[CH:39][C:38]([O:37][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:43][C:42]=1[Cl:44])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: C=CC[C@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve 4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (2.21 g, 8.52 mmol) in 25 ml of dry THF. Chilled to −78° C. Add LiN(TMS)2 (10.23 ml, 10.23 mmol). Stir for 30 min at same temperature. Add 5-Benzyloxy-2-bromomethyl-1,3-dichloro-benzene (3.10 g, 8.95 mmol) in 5 ml of THF. Let the reaction slowly warm to room temperature.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[C@@H:16]([CH3:26])[C:17](=[O:25])[CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S([N:43]=[N+:44]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:43](=[C:18]([C:17](=[O:25])[C@@H:16]([C@@H:12]1[C@@H:11]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH3:10])[C:14](=[O:15])[NH:13]1)[CH3:26])[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[N-:44]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of allyl (4R)-4-[(2R,3S)-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (6.52 g) and triethylamine (6.8 ml) in acetonitrile (50 ml) was added a lM solution (17 ml) of p-toluenesulfonyl azide in acetonitrile at 0°-5° C. and the mixture was stirred at the same temprature for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with hexane. The precipitates were filtered off. The filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (80 g) and eluted with a mixture of ethyl acetate and hexane (1:9 V/V) to give allyl (4R)-2-diazo-4-[(2R,3S)-3{(1R)-1-t-butyldimetylsilyloxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (3.78 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:9]1)=O)(C)(C)C.[CH3:39][O:40][CH2:41][CH2:42][Cl:43].C([O-])([O-])=O.[K+].[K+].Cl>CC(N(C)C)=O>[ClH:43].[CH3:39][O:40][CH2:41][CH2:42][O:26][C:22]1[CH:21]=[C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C@H:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COCCCl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3cccc(O)c3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCCOc1cccc(-c2cccc([C@H]3CCNC[C@@H]3OCc3ccc4ccccc4c3)c2)c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of the title D compound in Example 13, (3R*,4R*)-4-(3′-hydroxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (80 mg, 0.16 mmol), 2-chloroethyl methyl ether (57 μL, 0.62 mmol), K2CO3 (29 mg, 0.21 mmol), Kl (16.6 mg, 0.1 mmol) and dimethylacetamide (1.5 mL) is stirred under argon for 16 h at 75° C. After the addition of a second portion of 2-chloroethyl methyl ether (35 μL, 0.38 mmol) and K2CO3 (44 mg, 0.32 mmol) stirring is continued for 18 h at 75° C. The mixture is filtered and the filtrate evaporated in vacuo. HCl (5M in 2-propanol, 1 mL, 5 mmol) is added to the crude residue and the mixture is stirred for 45 min. at RT. The reaction mixture is evaporated in vacuo and the residue purified using preparative HPLC (H2O/CH3CN). The combined pure fractions are treated with solid K2CO3 and CH3CN is removed in vacuo. The aqueous layer is extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. The residue is stirred with HCl (5M in 2-propanol, 1 mL, 5 mmol) for 30 min. at RT. Evaporation of the solvent affords (3R*,4R*)-4-[3′-(2-methoxy-ethoxy)-biphenyl-3-yl]-3-(naphthalen-2-ylmethoxy)-piperidine hydrochloride as a brownish amorphous solid: MS (LC/MS) 468.4 [M+H]+; retention time 5.85 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[CH2:19]2.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O)(=O)C>C(#N)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[CH2:19]3)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCN1Cc2cc(N)ccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN1Cc2cc(NCc3ccc(Cl)cc3)ccc2C1=O
Reaction time: 8 h
Yield: 16.1 %

Procedure:
Sodium triacetoxyborohydride (1.28 g, 6.10 mmol) was added to a stirred solution of 5-amino-2-ethyl-2,3-dihydro-isoindol-1-one (540 mg, 3.05 mmol), 4-chlorobenzaldehyde (854 mg, 6.10 mmol) and acetic acid (183 μl, 3.05 mmol) in anhydrous acetonitrile (12 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (0 to 20% ethyl acetate in dichloromethane) to yield the title compound as a light brown solid (148 mg, 16%). HPLC retention time 4.23 min. Mass spectrum (ES+) m/z 301 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[N:20]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:17]3[S:18][C:11]4[C:12](=[N:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]4[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=4[F:1])[CH:16]=3)=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: OB(O)c1ccc(Cn2cccn2)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(Cn5cccn5)cc4)sc23)c(F)c1
Yield: 64.9 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 0.300 g, 0.777 mmol) and 4-((1H-pyrazol-1-yl)methyl)phenylboronic acid (0.196 g, 0.971 mmol) using the procedure described for Example 94, Step A, to provide the product (210 mg, 36%) as a brown solid. LRMS (esi+) m/e 417 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:23](N=P(N(C)C)(N(C)C)N(C)C)(C)([CH3:25])[CH3:24].C(Br)C=C>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:23]=[CH2:24])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Agent: Cl
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20 C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH2:21])[C:12]=1[NH2:22]>FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>[NH:21]1[C:13]2[CH:14]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]3=[CH:11][C:12]=2[NH:22][C:1](=[O:8])[C:2]1=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc2ccccc2cc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Product: O=c1[nH]c2cc3ccccc3cc2[nH]c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
According to Step 1 of Reference Example 10-3, diethyl oxalate (3.4 mL, 25 mmol) and ytterbium trifluoromethanesulfonate (196 mg, 0.32 mmol) were added to naphthalene-2,3-diamine (1.0 g, 6.3 mmol) and the mixture was stirred at 80° C. for 2 hours. After water was added to the reaction mixture, the precipitate was washed with ethanol. Thus, benzo[g]quinoxaline-2,3(1H,4H)-dione (1.4 g, yield: 99%) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH:13]([O-])=[O:14].[Na+].C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH:13]=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)cc1Cl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A slow stream of CO was passed into a suspension of methyl 4-bromo-2-chlorobenzoate (1.50 g, 0.00601 mol), bis(triphenylphosphine)palladium(II) chloride (80 mg, 0.0001 mol), sodium formate (613 mg, 0.00902 mol), and dry DMF (10 mL). The mixture was vigorously stirred at 110° C. for 2 h. After cooling, the mixture was treated with aqueous Na2CO3 solution and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with AcOEt-hexane to give the product as a colorless oil (becomes a white solid when stored in a refrigerator).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=Cc2cc(OC)c(C(C)C)c(OC)c2)cc1
Yield: 63 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 4-anisaldehyde in 63% yield as the same procedure as described in example 5(b). 1H NMR (CDCl3, ppm): δ 1.31 (d, J=7.1 Hz, 6H), 3.51-3.74 (m, 1H), 3.86 (s, 3H), 3.91 (s, 6H), 6.71 (s, 2H), 6.84-7.09 (m, 4H), 7.39-7.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(O)=O.[Na+].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>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Cl)ncn1
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: O=C([O-])[O-]
Solvent: CC#N
Product: COc1ccccc1-c1cc(Cl)ncn1
Temperature: 80 °C

Procedure:
To a 250 ml round bottomed flask was added 4,6-dichloropyrimidine (2.67 g, 17.95 mmol), 2-methoxyphenyl boronic acid (3.00 g, 19.7 mmol), acetonitrile (50 ml) and sodium carbonate (2.95 g, 26.9 mmol). The mixture was sparged with nitrogen for 15 minutes, Pd(PPh3)4 (0.48 g, 0.41 mmol) was then added, and the resulting yellow mixture was heated under an atmosphere of nitrogen at 80° C. for 48 hours. After cooling, the solution was diluted with aqueous NaHCO3 and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuum. Purification of the residue by silica gel chromatography (2 to 5% ethyl acetate/hexane) afforded 4-chloro-6-(2-methoxy-phenyl)-pyrimidine as a white solid. Yield: 2.5 g
Reaction SMILES: [CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][NH+:8]=1.CS(O)(=O)=O.[CH2:18]1[S:20][CH2:19]1>CC1C=CC=CN=1.O>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[SH:20][CH2:19][CH2:18][N+:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6]
Reactant: C1CS1
Reactant: Cc1cccc[nH+]1
Agent: CS(=O)(=O)O
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: Cc1ccccn1
Product: Cc1cccc[n+]1CCS
Temperature: 55 °C
Reaction time: 21 h
Yield: 85 %

Procedure:
To a suspension of 2-methylpyridinium methanesulfonate in 2-methylpyridine prepared by the addition of methanesulfonic acid (0.65 mL, 0.010 mol) to cold 2-methylpyridine (2.17 mL, 0.022 mol) was added ethylene sulfide (0.655 mL, 0.011 mol). The reaction mixture was stirred under a nitrogen atmosphere at 55° C. for 21 h, cooled to 23° C. and diluted with water (5 mL). The aqueous solution was washed with ether (6×4 mL) pumped to remove traces of organic solvents and poured on top of a column (2.5×10.0 cm) of μ-bondapak C-18. The column was eluted with water and lyophilization of the appropriate fractions gave 2.13 g (85%) of the title compound, ir (film) νmax : 2520 (SH), 1623 (pyridinium) 1574, 1512, 1485, 1412, 1195 (sulfonate), 1038 cm-1, 1Hmr (DMSO-d6 +D2O) δ: 2.37 (3H, s, CH3SO3-), 2.83 (3H, s, CH3 on pyridinium), 3.09 (2H, J=6.9 Hz, CH2S), 4.71 (2H, t, J=6.9 Hz, CH2N+), 7.93 (2H, m, Hm of pyridinium), 8.44 (1H, m, Hp of pyridinium), 8.89 (1H, m, Ho of pyridinium), uv (H2O) λmax : 266 (ε3550) m μ.
Reaction SMILES: Cl.O[NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16](=[CH:24]O)[C:17](=[O:23])[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16]2[CH:24]=[N:3][O:23][C:17]=2[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnoc1C2

Procedure:
Prepared as described in Example 5 using hydroxyamine hydrochloride and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11](C(OCC3C=CC=CC=3)(O)C)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[I-].[Na+].[CH3:40][C:41](C)=[O:42]>C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[CH:41]([OH:42])[CH3:40])=[CH:18][CH:19]=1
Reactant: CC(C)=O
Reactant: COc1ccc(COc2ccc(C(C)(O)OCc3ccccc3)cc2OCc2ccc(OC)cc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cccc(C(C)O)c2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 3,4-diacetoxy-ω-chloroacetophenone (2) (1.08 g: 4 mMol.) in acetone (11 ml) keeping at 0° C. is added sodium iodide (1.2 g: 2 Eq.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to give 3,4-diacetoxy-ω-iodacetophenone (3) (1.38 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[N:3]=1.CC(O)=O>CO.[Pd]>[NH2:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])nc1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(C)c1ccc(N)nc1C
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(2-methyl-6-nitropyridin-3-yl)propanoate (1.6 g, 6.7 mmol), 10% Pd/C (0.1 g) and AcOH (3 mL) in MeOH (50 mL) was stirred over night under 1 atm of H2 at room temperature. The mixture was filtered and concentrated to give the crude product ethyl 2-(6-amino-2-methylpyridin-3-yl)propanoate.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH2:4][F:5].[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([NH:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1)=[O:12])[CH2:2][F:1]
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
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
Solvent: O
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(CF)CF)c2)n1
Yield: 65.8 %

Procedure:
A solution 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (3.00 g, 9.31 mmol), 3-amino-1-methylpyrazole (1.83 g, 18.6 mmol), HATU (4.60 g, 12.1 mmol) and DIPEA (3.25 mL, 18.6 mmol) in DMF (12 mL) was stirred at RT overnight. Water (150 mL) was added and the solution partitioned with ethyl acetate (250 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired product (2.46 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[CH:9]=[C:10]([C:14]3[C:15]4[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][CH:13]=2)[S:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[CH:9]=[C:10]([C:14]3[C:15]4[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][CH:13]=2)[S:4][N:3]=1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(Nc4nc(Cl)ns4)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(Nc4nc(Cl)ns4)c3)c12
Reaction time: 1 h

Procedure:
A solution of ethyl 4-{3-[(3-chloro-1,2,4-thiadiazol-5-yl)amino]phenyl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (75 mg, 0.14 mmol) in TFA (1.0 mL) was stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue dissolved in ethyl acetate (2.0 mL). Potassium carbonate (2.0 mL, 4.0 mmol) was added and the reaction mixture was allowed to stir for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×3). The combined organic fractions were washed with water, dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by MPLC (0-10% methanol-dichloromethane) gave ethyl 4-{3-[(3-chloro-1,2,4-thiadiazol-5-yl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C7H14ClN6O2S [M+H]+: 401, found 401. 1H NMR (600 MHz, DMSO-D6) δ 13.0 (s, 1H), 11.4 (s, 1H), 8.94 (s, 1H), 8.35 (s, 1H), 7.81 (s, 1H), 7.63 (d, 1H, J 7.63 Hz), 7.53 (t, 1H, J=7.62 Hz), 7.39 (d, 1H, J=7.63 Hz), 3.85 (q, 2H, J=7.04 Hz), 0.85 (t, 3H, J=7.04 Hz).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[CH3:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[CH3:7])[CH2:12][CH2:13]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)CCN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CCN1CCN(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.3 %

Procedure:
Bromoacetyl bromide (0.52 ml, 6.0 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperazine hydro-chloride from Example E4 (1.5 g, 5.7 mmol) in dichloromethane (20 ml) and triethylamine (3.57 ml, 25.6 mmol) at 0° C. The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (220 mg, 13%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[CH:20][C:21]([N+]([O-])=O)=[CH:22][C:6]=2[N:5]=1.COCC1NC2C=CC([N+]([O-])=O)=CC=2[N:30]=1.CC1C=CC(S(Cl)(=O)=O)=CC=1.CC(C)([O-])C.[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:6]=2[N:5]=1
Reactant: COCc1nc2cc([N+](=O)[O-])ccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: COCc1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1nc2ccc(N)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
2-(Methoxymethyl)-5-nitro-1-tosyl-1H-benzo[d]imidazole. 2-(Methoxymethyl)-5-nitro-1H-benzo[d]imidazole (1.23 g, 5.94 mmol) and 4-methylbenzene-1-sulfonyl chloride (1.358 g, 7.12 mmol) were dissolved in tetrahydrofuran (50 mL) and sodium tert-butoxide (1.141 g, 11.87 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into a separatory funnel containing water and 50% ethyl acetate. The organic layer was concentrated on a rotary evaporator nearly to dryness and purified on silica column eluting with 0-50% ethyl acetate in hexane. The fractions containing product were concentrated on a rotary evaporator to give the desired product as white solid (0.9 g, 42% yield). MS (ESI) m/z 362.3 [M+1]+.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]=2[N:28]=1)(=O)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.O>CN1C(=O)CCC1>[CH:29]1([NH:32][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:9]=3[N:28]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(S(C)(=O)=O)ncc12
Reactant: NC1CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 77.9 %

Procedure:
methyl 3-(methylsulfonyl)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 117 mg, 0.298 mmol) was mixed in a vial with cylopropylamine (3.0 eq, 62 ul, 0.89 mmol) in NMP (2 ml). The mixture was stirred at 60° C. for 50 minutes. Water was added and the resulting solid filtered. The material was suspended in AcOEt/hexanes and filtered to afford methyl 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid (86 mg, 78% yield). LCMS (ES): >95% pure, m/z 371 [M+1]+.