Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21](=[N:27]O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[CH2:10][C:11]1[O:13][N:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=1
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2c(F)cc(F)cc2F)n1
Yield: 18.5 %

Procedure:
This compound was prepared according to General method 2 with (step I) 2-(2,4,6-trifluorophenyl)acetic acid (0.360 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.1002 g (19%) of ethyl 5-(2,4,6-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:21]([C@@H:24]3[CH2:29][C@@H:28]4[C@@H:26]([CH2:27]4)[N:25]3C(OC(C)(C)C)=O)[NH:22][CH:23]=1)[CH:13]=[CH:12]2>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:21]([C@@H:24]3[CH2:29][C@@H:28]4[C@@H:26]([CH2:27]4)[NH:25]3)[NH:22][CH:23]=1)[CH:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc3cc(Br)ccc3c2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Brc1ccc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166.3 %

Procedure:
TFA (1.028 mL, 13.34 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 120) (606 mg, 1.334 mmol) in DCE (20 mL) and reaction was stirred at rt for 2 h. Then additional TFA (1 mL) was added and the reaction was stirred at rt for 4 h. The reaction was concentrated to dryness and the crude brown oil was dissolved into diethyl ether and concentrated under vacuum (2×) to yield a TFA salt of (1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (786 mg) as a yellow solid. The material was used without further purification. LC-MS retention time 2.558 min; m/z 352.03, 354.05 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 10.55 (br. s., 1 H), 8.02 (s, 1 H), 7.93 (d, J=1.5 Hz, 1 H), 7.72 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.8 Hz. 1 H), 7.59 (dd, J=8.8, 2.0 Hz, 1 H), 7.52 (dd, J=8.7, 1.6 Hz, 1 H), 7.44 (s, 1 H), 5.10 (dd, J=11.8, 7.3 Hz, 1 H), 3.49-3.54 (m, 1 H), 2.94 (td, J=12.7, 4.6 Hz, 1 H), 2.68 (dd, J=13.2, 7.2 Hz, 1 H), 2.06-2.14 (m, 1 H), 1.20-1.26 (m, 1 H), 1.00-1.09 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[O-:9][CH2:10][CH3:11].[Na+]>C(O)C>[CH2:10]([O:9][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: Clc1cc(I)ccn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(I)ccn1

Procedure:
To 2.00 g (8.35 mmol) 2-chloro-4-iodopyridine in 15 mL ethanol are added 3.4 mL (9.2 mmol) sodium ethoxide and stirred at reflux for 12 h. The solvent is evaporated in vacuo and the residue is partitioned between water and DCM. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel; DCM/MeOH gradient 100/0→96/4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[CH2:19].ClCCl.C(N(CC)CC)C>CN1CCCC1=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:19]=[CH:18][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(I)cc1-c1ccccc1
Reactant: C=Cc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1
Temperature: 80 °C
Yield: 84.4 %

Procedure:
A mixture of the 4-iodo-2-phenylbenzoic acid methyl ester (6.11 g, 18.1 mmol), prepared as in Example 210C, 3-vinylpyridine (2.85 g, 27.1 mmol), prepared as in Example 210E, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed to dichloromethane (1:1) (444 mg, 0.543 mmol) and triethylamine (5.05 g, 36.2 mmol), in 1-methyl-2-pyrrolidinone (30 mL) was degassed with nitrogen and heated at 80° C. for 18 hours. The reaction mixture was diluted with ether, filtered through silica gel, and rinsed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate-hexane) to give the title compound (4.82 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[C:31](=[O:33])=[O:32].OS(O)(=O)=O>C1COCC1.C(OCC)C>[F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[C:31]([OH:33])=[O:32]
Reactant: COc1cc(F)ccc1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COc1c(F)ccc(F)c1C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 1,4-difluoro-2-methoxybenzene (i-6a) (2.88 g, 20 mmol) in THF (5 mL) was added to a solution of LDA freshly prepared from n-BuLi (10M solution in hexane, 2.2 mL, 22 mmol) and diisopropylamine (2.28 g, 22.8 mmol) in THF (20 mL) at −60° C. After 30 min, a freshly prepared solution of CO2 in diethyl ether (20 mL) was quickly added. Then aq. H2SO4 was added, and the resulting precipitate was collected and washed with H2O, and dried to give the title compound (i-6b) as white crystals. LCMS (ESI) calc'd for C8H6F2O3 [M+H]+: 189. found: 189.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][S:7][CH2:8][C:9]=1[NH:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([NH:10][C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(N[C@H](C)c2ccccc2)CSC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CSC[C@H]1N[C@H](C)c1ccccc1
Reaction time: 20 h
Yield: 27.9 %

Procedure:
A solution of crude (R)-4-(1-Phenyl-ethylamino)-2,5-dihydrothiophene-3-carboxylic acid methyl ester (2.82 g, ca. 9.1 mmol) was dissolved in trifluoroacetic acid (50 mL) and treated with triethylsilane (4.4 mL, 27.4 mmol). The mixture was stirred for 20 h , when TLC indicated residual starting material. Additional triethylsilane (1.5 mL) was added and the mixture was heated at reflux for 3 h , then was cooled and concentrated. The residue was dissolved in water and adjusted to pH 10 with 50% sodium hydroxide. The mixture was extracted with ether, and the combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (15-30% diethyl ether/petroleum ether) to provide the product as a colorless oil (673 mg, 28%). 1H NMR (300 mHz, CDCl3) δ7.33 (m, 4H), 7.27 (m, 1H), 3.84 (q, J=6.6 Hz, 1H), 3.73 (s, 3H), 3.61 (m, 1H), 3.1-3.0 (m, 3H), 2.80 (dd, J=11.0, 5.8 Hz, 1H), 2.54 (dd, J=11.0, 6.6 Hz, 1H), 1.37 (d, J=6.6 Hz, 3H), ESI MS: (M+H)+=266.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C.[ClH:10]>CO>[Cl:10][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: Cl
Reactant: Cc1ccc(O)cn1
Solvent: CO
Product: Cc1ccc(O)c(Cl)n1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Hydroxy-2-methylpyridine (1-014-01) (27.01 g) was dissolved in conc. hydrochloric acid (200 mL) and to the reaction mixture was bubbled chlorine gass at 68 to 74° C. After the reaction mixture was stood overnight, the volatile was removed by bubbling nitrogen gas. The reaction mixture was evaporated under reduced pressure to give the crystal residue. The crystal residue was dissolved in methanol, and treated with active charcoal. After recrystallization, the desired 2-chloro-3-hyroxy-6-methylpyridine (1-014-02) (23.96 g, 67.3%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].CCO>CC(O)=O.[Fe]>[NH2:11][C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(C=O)c1N
Temperature: 25 °C
Yield: 64 %

Procedure:
Iron powder (40 g) was slowly added to a stirred solution of 3-methoxy-2-nitrobenzaldehyde (1) (70 g, 386 mmole) in AcOH gal. (100 mL) and EtOH abs. (400 mL). The reaction was cooled using an ice bath followed by addition of con. HCL (1 mL). The reaction became exothermic. After stabilization of the reaction temperature, the reaction was heated to reflux. The reaction reached completion after ca. 20 minutes according to LCMS. The reaction mixture was cooled to RT and filtered. The filtrate was evaporated to a thick brown syrup. The dark residue was dissolved in EtOAc (500 mL) and water (200 mL). The mixture was basified with NaOH 6M to ca. pH 10. The mixture was filtered over celite and the layers separated. The organic layer was washed with NaHCO3 (2×100 mL), water (2×100 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to a dark amber oil. The oil was dried in vacuo to give 95% pure product 2-amino-3-methoxybenzaldehyde in 64% yield (37.2 g, 246 mmole).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2([CH2:20][CH2:21][N:44]3[CH2:43][CH2:42][C:41]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:18][CH:17]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)cc3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride to give the title compound: Rf =0.36 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:9][CH2:10][C:11]#[CH:12])CCS)([O-:3])=[O:2].Cl[CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[N+:1]([CH:4]=[C:5]([NH:9][C:10]#[C:11][CH3:12])[NH:19][CH2:18][CH2:17][S:16][CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)([O-:3])=[O:2]
Reactant: C#CCNC(=C[N+](=O)[O-])CCS
Reactant: ClCc1nccs1
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
The product of Step A is reacted in a non-reactive solvent with about an equimolar amount of 2-chloromethylthiazole and about one equivalent of base, and the title product is thereby produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:39]([CH:36]3[CH2:37][CH2:38][N:35]3[CH:32]3[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]3)=[O:40])[C@H:13]([C:16](=[O:17])[NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Cl)cc3)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccc(Cl)cc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(4-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7B and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(4-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (73%). MS ISP (m/e): 592.3/594.2 (100/40) [(M+H)]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=[O:3])[CH3:2].C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][CH:14]=2)(=[O:3])[CH3:2].[CH3:2][C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22]([CH3:23])=[O:24])[CH2:7][CH2:8][N:9]1[C:10]2[N:11]=[C:12]([NH2:19])[N:13]=[CH:14][C:15]=2[N:16]=[CH:17]1)=[O:3]
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine (15.4 g, 43 mmole), 5% palladium on carbon (6.16 g), triethylamine (6.6 ml, 47 mmole) and ethyl acetate (77 ml) was stirred at 50° C. under a hydrogen atmosphere at 1 bar pressure in an autoclave for 3 to 5 hours. After completion of the reaction the mixture was removed from the autoclave which was washed out with ethyl acetate (30 ml) keeping the washings at 50° C. The main reaction mixture was filtered through a celite bed followed by the washings and finally with ethyl acetate (30 ml). Water (46 ml) was added to the combined ethyl acetate filtrate plus washings. The ethyl acetate was evaporated to dryness to leave a crude white solid. This was recrystallised from n-butanol (62 ml), stirring the cooled solution at 0 to 5° C. for 3 h before filtration. The product was filtered off and washed with the mother liquors. The solid was reslurried in n-heptane (50 ml) stirred for 30 minutes and filtered. The product was dried at 40° C. for 16 h under vacuum.
Reaction SMILES: C(N[C:6]([C:8]1[S:12][C:11]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:10]=2[C:9]=1[CH:18]=[N:19][NH2:20])=[O:7])(C)(C)C>OS(O)(=O)=O>[CH3:17][C:14]1([CH3:16])[CH2:13][C:11]2[S:12][C:8]3[C:6](=[O:7])[NH:20][N:19]=[CH:18][C:9]=3[C:10]=2[CH2:15]1
Reactant: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=NN)c2C1
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2sc3c(=O)[nH]ncc3c2C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A solution of 131g (3.8 g, 13.0 mmol) in 30% H2SO4 (100 mL) was heated at reflux for 16 h. See FIG. 15. The reaction mixture was cooled to room temperature and extracted with dichloromethane (3×200 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 131h as a yellow solid (1.72 g, 60%). MS-ESI: [M+H]+ 221.0
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][C:22]([C:24]2([OH:34])[CH2:33][CH2:32][C:27]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:26][CH2:25]2)=[N:21][CH:20]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:5][C:4]1[CH:6]=[C:7]([C:19]2[S:23][C:22]([C:24]3([OH:34])[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(N)cc(-c2cnc(C3(O)CCC4(CC3)OCCO4)s2)c1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 8.58 mmol), the product of Step 2 (2.75 g, 8.58 mmol), X-Phos (0.409 g, 0.858 mmol), cesium carbonate (8.39 g, 25.7 mmol), and Pd2(dba)3 (0.393 g, 0.429 mmol) were placed in a flask flushed with Argon. Degassed Dioxane (30 ml) and Water (3 mL) were added and the reaction was heated to 100° C. for 40 h. The reaction was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification via flash chromatography (40%-100% EtOAc:hexanes) afforded 8-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (1.93 g, 65%) as a brown foam. MS ESI: [M+H]+ m/z 347.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[S:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].[OH:37]OS([O-])=O.[K+]>CC(C)=O.O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[S:14][C:15]([S:18]([CH3:19])=[O:37])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2]
Reactant: O=S([O-])OO
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)s1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)s1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (306.2 mg, 0.576 mmol) and oxone (531 mg, 0.864 mmol) in acetone (3 mL) and water (3 mL) was stirred at RT for 4 hrs. The reaction mixture was diluted with 30 mL of water which was stirred for 30 minutes. The solid was collected to give the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (264.5 mg, 77% yield). MS (ES+) m/z: 548.08 (M+H); HPLC retention time: 3.296 min (analytical HPLC Method F).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20])(=O)C.C[Si]([C:26]#[N:27])(C)C.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOC(C)=O>[NH2:27][CH2:26][C:8]1([OH:20])[C:7]2[C:15](=[C:16]([CH3:19])[C:17]([CH3:18])=[C:5]([OH:4])[C:6]=2[CH3:21])[O:14][C:10]2([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)C(O)(CN)CC1(CCC1)O2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate (2 g), Znl2 (100 mg) and trimethylsilyl cyanide (4 mL) was stirred at 70° C. for 2 h. A homogeneous solution was obtained. The solution was cooled down to room temperature, and THF (30 mL) was added, followed by 1 g of lithium aluminum hydride. After stirring at 60° C. for 3 h, the solution was cooled down and EtOAc was added to destroy excess lithium aluminum hydride. The mixture was poured into water and extracted with EtOAc. The EtOAc was washed with water and dried. After evaporation a white solid was obtained (1 g), which was washed with DCM to give 4-(aminomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol. 1H-NMR (300 MHz, CDCl3+CD3OD): δ=2.85 (AB, J=13.44 Hz, 2H), 2.36 (s, 2H), 2.35-1.60 (m, 6H), 2.11 (s, 9H) ppm. 13C-NMR (75 MHz, CDCl3+CD3OD) δ=146.82, 145.54, 124.91, 123.75, 121.01, 120.48, 76.49, 75.64, 50.07, 44.97, 34.46, 32.36, 13.75, 13.31, 12.50, 12.22 ppm. MS: (m/z)=260 (M+−OH).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][C:28](=[O:30])[CH3:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.N1C=CC=CC=1.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([S:42]([N:1]2[CH:5]=[C:4]([C:6]3[CH:32]=[CH:31][C:9]4[N:10]([C:13]5[CH:14]=[C:15]([NH:27][C:28](=[O:30])[CH3:29])[CH:16]=[C:17]([C:19]6[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=6[F:26])[CH:18]=5)[CH:11]=[N:12][C:8]=4[CH:7]=3)[CH:3]=[N:2]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(S(=O)(=O)C5CC5)c4)ccc32)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the compound of Example 326 (50 mg, 0.116 mmol) in DCM was added pyridine (0.5 ml) followed by cyclopropanesulfonyl chloride (20 mg, 0.139 mmol, 1.2 eq.). The mixture was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 90% yield (42 mg). 1H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.74-7.62 (m, 4H), 7.49 (s, 1H), 7.17-7.08 (m, 2H), 3.0 (m, 1H), 2.2 (s, 3H), 1.1 (d, 4H); LC-MS (ESI): Calculated mass: 533.5; Observed mass: 534.1 [M+H]+ (rt: 1.61 min).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[N:4]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:16]1([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:13]([O-:15])=[O:14])[N:4]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2nc(CBr)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2nc(CN3CCOCC3)ccc12

Procedure:
460 mg (1.72 mmol) of 2-bromomethyl-5-nitroquinoline and 0.54 ml (6.2 mmol) of morpholine are dissolved in 150 ml of toluene. After 1.07 g (7.74 mmol) of potassium carbonate is added, the reaction mixture is allowed to reflux for 2 hours. Potassium carbonate is filtered off, and the filtrate is concentrated by evaporation. After purification on silica gel with hexane-ethyl acetate (0-100%), 190 mg (40% of theory) of the product is obtained.