Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: COCCOC
Solvent: O
Product: Cn1nccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-4), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (321 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (159 mg, 31%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)N1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Reactant: N
Solvent: CC(C)O
Product: CC(=O)N1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Temperature: 110 °C

Procedure:
1-{4-[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-piperazin-1-yl}-ethanone (13.2 g, 0.029 mol) was dissolved in isopropyl alcohol (100 mL) into a Parr pressure reactor. The vessel was cooled to −78° C. and saturated with ammonia gas and sealed. The reaction was heated for 19 h at 110° C., at which point the reaction was cooled and the solvent concentrated in vacuo. The crude product was purified via silica gel chromatography eluting with 5-10% MeOH (7M NH3): CH2Cl2 to yield the title compounds as an off white solid; MS (ES+): m/z 440.89 (100) [MH+], 441.89 (20) [MH++]; HPLC: tR=0.46 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.09 (s, 3H) 2.28-2.48 (m, 6H) 2.54-2.71 (m, 2H) 2.80-2.99 (m, 1H) 3.27-3.43 (m, 1H) 3.43-3.54 (m, 2H) 3.56-3.70 (m, 2H) 7.02 (d, J=5.05 Hz, 1H) 7.16 (d, J=5.05 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH3:25]>C(O)C>[NH2:25][CH:12]=[C:6]([C:4](=[O:5])[C:3]1[CH:16]=[C:17]([F:24])[C:18]([Cl:23])=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=1[Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: N
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
38 g of the product from Example 1 are intitially introduced into 40 ml of ethanol. A mixture of 8 ml of concentrated NH3 solution in 25 ml of ethanol is added dropwise with ice cooling. The mixture is stirred for 2 hours at room temperature and the phases are then separated. The organic phase is washed with water and dried. 38.3 g of the title compound remain on concentration.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[C:33]3[C:32]4[CH:31]=[C:30]([C:34]5[CH:39]=[CH:38][C:37]([O:40][C:41]6[N:46]=[CH:45][CH:44]=[CH:43][N:42]=6)=[CH:36][C:35]=5[Cl:47])[C:29]([F:48])=[CH:28][C:27]=4[N:26]=[CH:25][C:24]=3[N:23]=[C:22]2[CH3:49])[C@@H:17]([F:50])[CH2:16]1)=O)(C)(C)C.CO.C(Cl)Cl>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:47][C:35]1[CH:36]=[C:37]([O:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:38]=[CH:39][C:34]=1[C:30]1[C:29]([F:48])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:23]=[C:22]([CH3:49])[N:21]([C@H:18]4[CH2:19][CH2:20][NH:15][CH2:16][C@@H:17]4[F:50])[C:33]=3[C:32]=2[CH:31]=1
Reactant: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCNC[C@@H]1F
Reaction time: 3 h

Procedure:
TFA (20 ml) was added drop wise to a solution of (3S,4S)-tert-butyl-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate (10 g, 0.0164 mol) in dry DCM (150 mL) at 0° C. under N2 atmosphere. After addition completed, the reaction mixture allowed to RT and stirred for 3 h. The reaction was monitored by TLC (5% MeOH/DCM), after completion of reaction by TLC, the volatiles were concentrated under vacuum. The obtained residue was triturated with diethyl ether. The solid was filtered and dried under vacuum to afford TFA salt of 8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoropiperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline (11 g, quantitative). LCMS: 99.41%, m/z=507.1 (M+1) (Free base); HPLC: 96.43%, 6.002 min.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(C(=O)O)c(C)nc2c1
Agent: Br
Product: Cc1nc2cc(O)ccc2cc1C(=O)O
Temperature: 105 °C
Yield: 92 %

Procedure:
7-Methoxy-2-methylquinoline-3-carboxylic acid (100 mg, 0.46 mmol) was suspended in HBr (aq.) (48%, 5 ml) and heated at 105° C. overnight. The reaction was cooled to ambient temperature. The precipitate was collected by filtration and dried under high vacuum to afford the title compound as a yellow solid (86 mg, 91%).
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:9][N:8]([C:10](=[O:26])[C@@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[C@H:7]([C:27]([O:29][CH3:30])=[O:28])[CH2:6]1)C=C.SC1N=CC=CC=1C(O)=O>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][C:31]([C@@:5]23[CH2:9][N:8]([C@H:7]([C:27]([O:29][CH3:30])=[O:28])[CH2:6]2)[C:10](=[O:26])[C@@H:11]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:1][S:4]3)=[CH:36][CH:35]=1
Reactant: C=CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCC=C)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCC/C=C/CS2
Agent: O=C(O)c1cccnc1S
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCC=CCS2

Procedure:
A solution of (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)oct-7-enoyl)pyrrolidine-2-carboxylate (120 mg, 0.202 mmol) in Dichloromethane (50 mL) was purged with nitrogen for 30 min. And then Hoveyda-Grubbs Catalyst 2nd Generation (153 mg, 0.243 mmol) was added. The resulting green solution was heated to reflux for 5 h. The reaction was quenched with 2-Mercaptonicotinic acid (62.8 mg, 0.405 mmol) and washed with sat. Na2CO3, and brine. Dried over MgSO4, filtered, concentrated in vacuo. The brown residue was purified by Biotage column, eluted with gradient 5%˜50% EtOAc-Hexane to afford the desired product (3S,12R,14S,E)-methyl 12-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-11-thia-1-azabicyclo[10.2.1]pentadec-8-ene-14-carboxylate (94 mg, 0.150 mmol, 74.0% yield) as grenish foam.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:25][CH2:26][OH:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][O:27][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OCCN1CCOCC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCN1CCOCC1

Procedure:
The title compound, white solid, m.p.=135-137° C. and MS: m/e=369.3 (M+H−) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2-morpholin-4-yl-ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:21][CH2:22][S:23][CH3:24])[CH:10]([O:14]C1CCCCO1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:21][CH2:22][S:23][CH3:24])[CH:10]([OH:14])[C:11]([O:13][CH3:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(OC1CCCCO1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
A solution of Example 11B (0.25g, 0.68 mmol) and trimethylsilyldiazomethane (2.0M in hexanes, 15 mL) in THF at room temperature was stirred for 4 hours, treated with acetic acid (1 mL), and concentrated. The residue was dissolved in methanol, treated with p-toluenesulfonic acid (10 mg), and heated to 55° C. for 16 hours. The mixture was concentrated and purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product. MS (APCI(+)) m/e 294 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:5][C@H:4]1[OH:22].[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH2:2][C@H:3]3[CH2:7][N:6]([CH2:8][CH2:9][C:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=5)[N:13]=[CH:12][CH:11]=4)[CH2:5][C@H:4]3[OH:22])[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2nccc(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(CCN3C[C@H](CNCc4cc5c(cn4)OCCO5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a stirred solution of (3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.30 g, 1.0 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.165 g, 1.0 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.32 g, 1.5 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.12 g, 27%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=4.5 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.68 (d, J=4.5 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 7.02 (s, 1H), 4.61 (m, 1H), 4.38 (m, 4H), 4.20 (s, 2H), 4.15 (s, 3H), 3.60 (m, 8H), 3.42 (m, 1H), 3.25 (m, 1H), 2.82 (m, 1H). LC-MS (ES) m/e 452 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:40]=[N:39][C:38]2[N:13]([C@@H:14]3[O:37][C@H:27]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:21](OC(SC)=S)[C@H:15]3OC(SC)=S)[CH:12]=[N:11][C:10]=2[C:9]1=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[PH2](O)=O.C(N1CCCCC1)C.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[CH2:1]([N:8]1[CH:40]=[N:39][C:38]2[N:13]([C@@H:14]3[O:37][C@H:27]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:21]=[CH:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=S)O[C@@H]1[C@H](OC(=S)SC)[C@@H](COCc2ccccc2)O[C@H]1n1cnc2c(=O)n(Cc3ccccc3)cnc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: CC#N
Product: O=c1c2ncn([C@H]3C=C[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
An acetonitrile solution (1 mL) of N1,5′-O-dibenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine (314 mg, 0.5 mmol) was heated to 80° C. To this solution, an acetonitrile solution (1 mL) of N-ethylpiperidine hypophosphite (358 mg, 2 mmol) and 2,2′-azobisisobutyronitrile (16.4 mg, 0.1 mmol) were added, and the mixture was then stirred at 90° C. for one hour. After the reaction mixture was cooled, the reaction was terminated with the addition of water (3 mL). The reaction mixture was extracted by the addition of ethyl acetate (15 mL), and the resultant organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After purification by chromatography (using 12 g of silica gel and a mixed solvent of hexane and ethyl acetate (1:2) as an eluting solution), 150 mg of the intended product was obtained in a yield of 71% as a colorless oily material.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=1>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCCCOc1cccc(-c2ccnc(Cl)n2)c1
Product: CCCCOc1cccc(-c2ccnc(NCCc3ccc(O)c(OC)c3)n2)c1

Procedure:
Intermediate 46 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 394. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 2H) 6.85 (m, 1H) 672 (m, 2H) 5.51 (br s, 1H) 4.0 (t, 2H) 3.75 (s, 3H) 3.7 (m, 2H) 2.89 (t, 2H) 1.78 (d, 2H) 1.5 (d, 2H) (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[O:6][N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>O1CCCC1>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:17](=[O:18])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
To a stirred mixture of 3-isopropylisoxazole-5-amine (250 mg, 1.98 mmol) and potassium carbonate (634 mg, 4.59 mmol) in dry tetrahydrofuran (6 mL) was added phenyl chloroformate (341 mg, 2.18 mmol). The reaction mixture was stirred at room temperature for 3.5 h, then additional phenyl chloroformate (341 mg, 2.18 mmol) was added and stirring was continued for a further 15 h. The resulting mixture was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4, then concentrated under reduced pressure to give a yellow oil. Purification via silica gel chromatography eluting with 4% to 40% ethyl acetate in hexanes afforded phenyl 3-isopropylisoxazol-5-ylcarbamate as a colorless solid (330 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 7.76 (brs, 1H), 7.40-7.45 (m, 2H), 7.18-7.31 (m, 3H), 6.07 (s, 1H), 3.02 (septet, J=6 Hz, 1H), 1.28 (d, J=6 Hz, 6H); LC-MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[CH:13]([NH:16][C:2]1[N:7]=[C:6]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:9][CH:5]([CH3:6])[CH3:4])[N:3]=1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)N
Product: CC(C)Nc1nc(NC(C)C)c([N+](=O)[O-])c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 148.5 %

Procedure:
1.15 g (0.005 mol) of 2,4,6-trichloro-5-nitropyrimidine are dissolved in 50 ml of alcohol and the solution is then treated with 2.9 g (0.05 mol) of isopropylamine. The mixture is stirred for 3 hours at room temperature after the temperature has first risen to 35°C, and then it is evaporated. The residue is treated with 100 ml of water and extracted twice with ether. The ethereal extract is dried over MgSO4 for 4 hours, filtered, and evaporated, to yield 1.1 g of 2,4,6-tri-isopropylamino-5-nitro- pyrimidine as an oil; b.p. 185°C at 0.001 Torr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([OH:24])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a stirred solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (5 g) in methanol (10 ml) is added dropwise a solution of sodium hydroxide (2.6 g) in water (20 ml) at room temperature. After completing addition, the mixture is stirred for 30 minutes, diluted with water (300 ml) and extracted with ethyl ether (50 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid (3.5 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.CCOCC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=4)[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: OCC1CCC2CN(c3ncc(Cl)cc3Cl)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(OCC2CCC3CN(c4ncc(Cl)cc4Cl)CCN3C2)cc1
Yield: 87.3 %

Procedure:
A solution of 0.50 g (1.58 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(3,5-dichloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 40 mL of THF with 0.266 g (2.32 mmol) of 4-fluorophenol, 0.498 g (1.90 mmol) of triphenylphosphine, and 0.30 mL (1.90 mmol) of diethyl azodicarboxylate was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and treated with excess HCl(g) in ether. The solvent was evaporated and the residue washed repeatedly with 1:1 ethyl acetate:ether. The white powder was dissolved in chloroform, washed with 1M NaOH (2×), dried (magnesium sulfate), filtered and evaporated. The crude product was purified by flash silica gel chromatography with 50:50 ethyl acetate: hexane to give 0.566 g (87%) of title compound. mp (.HCl) 247–248° C. 13C NMR (base, CDCl3): δ 27.1, 29.0, 36.4, 49.0, 54.4, 54.8, 58.6, 60.7, 71.7, 115.36, 115.47, 115.59, 115.89, 122.3, 124.0, 138.2, 155.1, 155.6, 156.6, 158.8. HRMS calc for C20H22Cl2FN3O: 409.1124, found: 409.1141.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]([CH3:15])=[C:6]([CH:8](O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:16][CH3:17])=[CH:4][C:5]=1[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)c1cc(Cl)c(OC)cc1C
Product: CCOC(=O)C(Cl)c1cc(Cl)c(OC)cc1C
Yield: 99.3 %

Procedure:
A solution of ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-hydroxyacetate (Intermediate 3-6; 1.1 g, 4.25 mmol) in thionyl chloride (3.42 mL, 46.89 mmol) under nitrogen was stirred at 80° C. for 30 minutes. The reaction mixture was allowed to cool concentrated and diluted with water (20 mL), extracted with EtOAc (2×20 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford ethyl 2-chloro-2-(5-chloro-4-methoxy-2-methylphenyl)acetate (1.170 g, 99%) as a yellow gum.
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH2:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:19][C:18]=2[F:40])[CH:8]=1)[CH3:2].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH2:41]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:19][C:18]=2[F:40])[CH:8]=1)[CH3:42]
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=O)CC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=O)CC4CCNCC4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of tert-butyl 4-(2-(4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)-2-oxoethyl)piperidine-1-carboxylate (Example 35; 2 mg, 0.00336 mmol) in methylene chloride (3 mL) was added 2,2,2-trifluoroacetic acid (3.83 mg, 0.0336 mmol). The reaction was stirred for 4 hours at room temperature. The reaction mixture was concentrated to dryness to give the product as a clear oil. Yield: 1.2 mg (47%). LRMS (esi pos) m/e 495 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][NH2:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1>C(#N)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([CH2:18][NH:9][CH2:8][CH2:7][NH2:10])=[CH:16][CH:17]=1
Reactant: NCCN
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCCNCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 4.2 g (0.03 mol) of potassium carbonate and 10 ml (0.15 mol) of ethylenediamine in a 50 ml of flask placed in an ice bath, 4.8 g (0.03 mol) of 2-chloro-5-(chloromethyl)pyridine dissolved in 15 ml of acetonitrile was added dropwise and slowly for nearly 20 min. After addition, the ice bath was removed and then the mixture was stirred for 8 hours at room temperature. After the reaction was stopped, a large amount of water was added to dissolve potassium carbonate and ethylenediamine, and the mixture was extracted with dichlormethane. The lower organic phase was collected, dried, and evaporated to dryness (It was better to remove all of the ethylenediamine in the solvent since its presence would influence the following step). The obtained product was yellow oily liquid in 68% yield.