Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][C:28](O)=O)[CH2:23][CH2:22]2)[C:3]=1[Br:31].C[Si](C)(C)CCOC[N:38](COCC[Si](C)(C)C)C1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCCC([CH2:64][C:65]([O:67]CC)=[O:66])C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:64][C:65]([OH:67])=[O:66])[CH2:22]2)[C:3]=1[Br:31].[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][C:28]#[N:38])[CH2:23][CH2:22]2)[C:3]=1[Br:31]
Reactant: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Reactant: Nc1c(Br)c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Product: N#CCC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CC1
Product: Nc1c(Br)c(C2CCCC(CC(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
2-(3-(7-Amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetic acid was synthesized in a manner similar to the synthesis of 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetic acid, but with ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate. The reaction was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile as a four-isomer mixture. (m+H=480.1, retention time=3.51 min)
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:7].N.[Br:32]Br>ClCCl>[BrH:32].[CH2:6]([C:8]1([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][C:22]([Br:32])=[CH:21][CH:20]=4)[CH3:7]
Reactant: BrBr
Reactant: CCC1(CCC(=O)OC)CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: N
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: Br
Product: CCC1(CCC(=O)OC)CCC[N+]2=C1c1[nH]c3ccc(Br)cc3c1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
4.39 g. (10 mmoles) of 1-ethyl-1-(2'-methoxycarbonylethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-5-ium perchlorate are shaken with a mixture of 5 ml. of 10% aqueous ammonia and 50 ml. of dichloromethane. The phases are separated, the organic phase is dried over 10 g. of solid anhydrous sodium sulfate and filtered. The filtrate is admixed with 50 ml. of glacial acetic acid, and dichloromethane is distilled off in vacuo. 0.67 ml. (13 mmoles, 2.08 g.) of elemental bromine are added dropwise, under vigorous stirring, to the residue at 25° C. The reaction mixture is stirred at room temperature for 3 hours, the precipitated yellow, crystalline product is filtered off and dried. In this way 4.5 g. of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-5-ium hydrobromide are obtained; yield: 90%, m.p.: 127°-128° C. The NMR spectrum of the product has the characteristic bands as indicated in Example 7.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]([C:20](=[CH:26]OCC)[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>C(O)C>[NH2:19][C:18]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:10]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a stirred suspension of 4-fluorophenylhydrazine hydrochloride (9.76 g, 60 mmol) in ethanol (250 ml) was added triethylamine (9.2 ml, 62 mmol) and to the resulting amber solution was added ethyl 2-cyano-3-ethoxyacrylate (10.15 g, 60 mmol). The solution was heated at reflux temperature for 3.5 hours. The solution was allowed to cool to room temperature and after standing overnight the resultant solid was filtered off, washed with small amount of ethanol and then ether before being dried under vacuum to give the title compound (12.1 g) as an off white solid.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:15](=[O:19])(=[O:18])([OH:17])[OH:16].[Cl-].[Ba+2:21].[Cl-]>>[CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([O-:18])(=[O:17])=[O:16].[Ba+2:21].[CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([O-:17])(=[O:19])=[O:16]
Reactant: c1ccc2c(c1)ccc1ccccc12
Reactant: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [Cl-]
Product: O=S(=O)([O-])c1ccc2c(ccc3ccccc32)c1

Procedure:
Phenanthrene is sulfonated with concentrated sulfuric acid and then treated with barium chloride to obtain barium 2-phenanthrenesulfonate. The resulting barium salt is subjected to alkali fusion in an electric oven and then treated with hydrochloric acid to obtain 2-phenanthrol. 2-Phenanthrol is subjected to oxidative coupling in the presence of a copper-amine complex to synthesize racemic 1,1'-biphenanthryl-2,2'-diol (I). The resulting diol is reacted with optically active phenylethylamine and thiophosphoryl chloride to afford (±)-N((S)-1-phenylethyl)-1,1'-biphenanthryl-2,2'-diylthiophosphorylamide. Recrystallization of the racemate gives an optically active compound, which is then hydrogenolyzed with a reducing agent, such as lithium aluminum hydride, to give optically active 1,1'-biphenanthryl-2,2'-diol with an optical purity reaching nearly 100%.
Reaction SMILES: [CH2:1]([SiH:19]([Cl:21])[Cl:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)(C)C>[CH2:22]([Si:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([Cl:21])[Cl:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC[SiH](Cl)Cl
Reactant: CCCCCC
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCC[Si](Cl)(Cl)CCCCCC
Temperature: 50 °C
Reaction time: 25 h

Procedure:
Resultant n-octadecyldichlorosilane in an amount of 176.5 g (0.5 mol), 50.4 g of 1-hexane (0.6 mol) and 0.05 mol % of a H2PtCl2 ·6H2O solution in isopropanol (relative to n-octadecyldichlorosilane) were reacted in a flask with stirring at 50° C. for 25 hours to give n-hexyloctadecyldichlorosilane [(n--C6H13)(n--C18H37)SiCl2 ].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.CC(O)=O>[Zn].CO>[F:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a stirred mixture of 2-amino-5-fluoro-3-nitropyridine (2.46 g, 15.66 mmol) in a mixture of glacial HOAc (10 mL) and MeOH (20 mL) at 0° C. was added zinc dust (5.09 g, 78.3 mmol) portion-wise, and the mixture was allowed to warm slowly to rt. After stirring at rt for 15 h, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHCO3. The organic layer was separated and the aqueous layer was extracted with additional EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 5-fluoropyridine-2,3-diamine (1.13 g) as a solid which was not purified further. LCMS (ESI) m/z 128 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[OH:27]OS([O-])=O.[K+]>C(O)(=O)C.O>[CH3:1][S:2]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:19][CH:20]=2)[C:5](=[O:14])[C:6]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1)=[O:27]
Reactant: O=S([O-])OO
Reactant: CSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 2-(methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (2.1 g) in acetic acid (40 mL) was added a solution of oxone (registered mark) (4.02 g) in water (8 mL). The reaction mixture was stirred at room temperature for 2 hr, water was added thereto, and the precipitate was collected by filtration to give the title compound (1.68 g).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].[OH-:29].[Na+].OO>O1CCCC1.O.C(O)C>[OH:29][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: C=CCCCCn1c2ccccc2c2ccccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
200 ml of a solution of 9-borabicyclo[3.3.1]-nonane in tetrahydrofuran (0.5 mol/1) were initially taken in a thoroughly heated 500 ml three-necked flask. 100 mmol of N-(5-hexenyl)-carbazole in 100 ml of dry tetrahydrofuran were added dropwise. Thereafter, the mixture was stirred for 3 hours at room temperature and then 60 ml of ethanol, 20 ml of 6N sodium hydroxide solution and 40 ml of hydrogen peroxide (30% strength) were added in succession. The reaction mixture was then refluxed for one hour. It was then worked up by adding 200 ml of water and stripping off the tetrahydrofuran. The N-(6-hydroxyhexyl)-carbazole formed was extracted with ether and the ether extract was dried and evaporated. The resulting crude product was then recrystallized from 9:1 hexane/acetone. The N-(6-hydroxyhexyl)-carbazole was obtained in the form of white crystals in a 60% yield and had the following product characteristics:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=1.C([Li])CCCCC.CC([O-])=O.[Na+].CC(O)=O.C([O-])(=O)C.[Na+]>C1COCC1.O.C(O)(=O)C>[Cl:8][C:9]1[N:10]=[CH:11][C:12]([C:13]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C1CNCCNC1
Agent: CC(=O)[O-]
Agent: [Li]CCCCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Cl)nc1)N1CCCNCC1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A solution of homopiperazine (385.62 g, 3.85 mol) in THF (3.9 L) was cooled to an internal temperature of 0° C. and ethyl 6-chloronicotinate (285.82 g, 1.54 mol) was added in THF (0.57 L) over 5 min. After stirring for 10 minutes, n-hexyl lithium (2.3 M in hexane, 335 mL, 0.77 mol) was added to the resulting mixture, over 40 min. The resulting mixture was stirred for 2 h at 0° C., then warmed to 20° C. over 1 h. After an additional 15 h at 20° C., the resulting mixture was treated with 1M NaOAc/HOAc buffer (5 L) (prepared by diluting 47.35 g of sodium acetate and 253.2 mL of acetic acid with water to a total volume of 5 L).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][C:32]([NH:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].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>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[O:31][CH3:30])[CH:39]([CH3:41])[CH3:40])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indoline-1-carboxylate (1.41 g, 3.2 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate was dissolved in DMF (30 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (560 mg, 3.2 mmol), HATU (1.22 g, 3.2 mmol), and DIPEA (2.79 mL, 16 mmol) were added sequentially. The solution stirred for 3 h, diluted with EtOAc, washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated. The mixture was purified by silica gel chromatography to yield product (600 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30]C3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:36][O:37][CH2:38]CC(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:36][O:37][CH2:38][CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)=[O:5])=[N:26][N:27]=1
Reactant: COCCC(=O)NN
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 3-methoxypropanehydrazide (compound 143.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 444 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH:4]=[CH:3]1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:22]2)=CC=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[S:22])[CH:4]=[CH:3]1
Reactant: Cn1ccc(=O)c2ccccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: Cn1ccc(=S)c2ccccc21
Reaction time: 1 h
Yield: 165.4 %

Procedure:
Under an inert atmosphere, 1 g of 1-methyl-4-quinolone was dissolved in 20 ml of benzene and then under bigorous stirring, 1.27 g of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson's reagent) was added all at once with stirring for 1 hour at reflux. After cooling and concentrating to dryness by distilling under reduced pressure, the 2.5 g of residue were chromatographed on silica and eluted with a mixture of methyl chloride and methanol (9/1) to obtain 910 mg of the expected product melting at 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][O:3]1.Cl.[CH3:14][NH:15][O:16][CH3:17].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O.CN(C=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8]([C:5]1([CH3:11])[CH2:4][O:3][C:2]([CH3:1])([CH3:12])[O:7][CH2:6]1)=[O:10]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C1(C)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a mixture of 2,2,5-trimethyl-1,3-dioxane5-carboxylic acid (1.0 g, 5.74 mmol) and DMF (10 mL) were added N,O-dimethylhydroxylamine hydrochloride (0.84 g, 8.6 mmol), 1-hydroxybenzotriazole hydrate (1.32 g, 8.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid (1.651 g, 8.61 mmol) and triethylamine (2.39 mL, 17.2 mmol) under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give N-methoxy-N,2,2,5-tetramethyl-1,3-dioxane5-carboxylic acid amid (1.08 g, yield: 86%) as colorless oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][C@H:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CON=C1C[C@@H](C(=O)N[C@H]2CC[C@H](O)CC2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and trans-4-aminocyclohexanol, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=436.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([Cl:17])[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([Cl:17])[C:14]([C:18]([F:20])([F:21])[F:19])=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Nc2ccc(Cl)c(Cl)c2)nc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.86 g of 3,4-dichloroaniline dissolved in 10 ml of dioxane are added to 6.51 g of 2,4-dichloro-5-trifluoromethyl-pyrimidine in 40 ml of dioxane at ambient temperature. Then 6 ml of 5 M potassium carbonate solution are added and the mixture is stirred for three days at ambient temperature. It is then filtered through Alox B (20 ml) and washed with dioxane. The filtrate is concentrated by evaporation, the residue dissolved in 50 ml methylene chloride and this solution is cooled in a bath of dry ice and acetone. The precipitate is suction filtered and the filtrate is cooled again. After suction filtering again the precipitates are combined and the filtrate is concentrated by evaporation. The residue is separated by chromatography through an RP18 column (gradient: acetonitrile: H2O=20:80 to 80:20).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O.[H][H]>[Pt]=O.C(O)(=O)C>[NH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:1])[CH2:9][CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2cccnc12
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Nc1cccc2c1NCCC2
Yield: 71.4 %

Procedure:
A mixed solution of 8-nitroquinoline (25.0 g), platinum oxide (600 mg) and glacial acetic acid (300 ml) was stirred at room temperature for 4 hours under the atmosphere of hydrogen at 5 atm. The reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. Then, the solution was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography to give the title compound as a reddish brown oil (15.2 g).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:18][O:17][C:15]([C:14]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([OH:12])[C:4]2[C:5](=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=2)[N:11]=1)=[O:16]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)C#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A stirred mixture of methyl-2-amino-4-chlorobenzoate (2.50 g, 13.5 mM) and dimethyl acetylenedicarboxylate (2.05 g, 14.4 mM) in t-butanol (22 mL) was refluxed for 7 hours under a nitrogen atmosphere. After adding additional dimethyl acetylenedicarboxylate (1.16 g, 8.13 mM) and refluxing another 2.5 hours, the reaction mixture was allowed to cool to room temperature and potassium t-butoxide (1.56 g, 13.9 mM) was added in one portion. A precipitate formed and the resulting mixture was refluxed for 1.5 hours. The mixture was cooled to room temperature and filtered to separate the solids, which were washed with t-butanol and ether. The solids were dissolved in water and acidified with 1N sulfuric acid to form a precipitate. The resulting mixture was extracted with methylene chloride and the combined extracts were washed with brine and water, dried (MgSO4), filtered and concentrated to give a green solid. Recrystallization of this material from methanol provided dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.15 g, 28.94) as an off-white solid, mp 232-233° C.; MS (Cl):296 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C@@H:14]([O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[C@@H:12]3O)[C:6]=2[N:7]=1.C(N(S(F)(F)[F:39])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C@@H:14]([O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[C@H:12]3[F:39])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@@H]3O)c2n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@H]3F)c2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of the compound from Step G (0.24 g, 0.51 mmol) in CH2Cl2 (5 mL) and pyridine (0.8 mL) at −60° C. was added diethylaminosulfur trifluoride (DAST; 0.27 mL) dropwise under Ar. The solution was stirred at −60° C. for 0.5 h, at 0° C. overnight and at room temperature for 3h. The mixture was diluted with CH2Cl2 (25 mL) and poured into saturated aqueous NaHCO3 (15 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and evaporated. The residue was purified on a silica gel column with a solvent system of hexanes/EtOAc: 5/1 to give the title compound (45 mg) as a pale yellow foam.