Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][C:34]1([CH2:37][OH:38])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH2:33][C:34]5([CH2:37][OH:38])[CH2:36][CH2:35]5)[CH3:31])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CNCC1(CO)CC1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CC1(CO)CC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(1-hydroxymethyl-cyclopropylmethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and (1-methylaminomethyl-cyclopropyl)-methanol following General Procedure B.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(-c2ncccc2[N+](=O)[O-])c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2[N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a suspension of 3-(3-nitropyridin-2-yl)aniline (400 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (616 mg) and diisopropylethylamine (0.745 ml) in dichloromethane (18.6 ml) was added 1-methyl-2-chloropyridinium iodide (618 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-nitropyridin-2-yl)phenyl)guanidine (730 mg).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:12]([C:61]2[CH:62]=[C:63]([CH3:67])[CH:64]=[CH:65][CH:66]=2)[C:13]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([N:26]([C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]6OCC[O:41]6)[CH:35]=5)[C:27]5[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=5)=[CH:20][CH:21]=4)[C:16]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl>CC(C)=O>[CH2:53]([C:16]1([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:17]2[CH:18]=[C:19]([N:26]([C:34]3[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=3)[CH:40]=[O:41])[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[CH:20]=[CH:21][C:22]=2[C:23]2[C:15]1=[CH:14][C:13]([N:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1])[C:61]1[CH:62]=[C:63]([CH3:67])[CH:64]=[CH:65][CH:66]=1)=[CH:25][CH:24]=2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(N(c3cccc(C)c3)c3cccc(C4OCCO4)c3)ccc2-c2ccc(N(c3cccc(C)c3)c3cccc(C4OCCO4)c3)cc21
Agent: Cl
Solvent: CC(C)=O
Product: CCCCCCCCC1(CCCCCCCC)c2cc(N(c3cccc(C)c3)c3cccc(C=O)c3)ccc2-c2ccc(N(c3cccc(C)c3)c3cccc(C=O)c3)cc21
Yield: 90.7 %

Procedure:
To a three-neck round-bottom flask, were added 34.0 g N2,N7-bis(3-(1,3-dioxolan-2-yl)phenyl)-9,9-dioctyl-N2,N7-di-m-tolyl-9H-fluorene-2,7-diamine and in 1000 mL acetone. 189.5 mL 2 M hydrochloric acid solution was added slowly to the reaction mixture through an addition funnel. The reaction was monitored by TLC. After the reaction was done showed by TLC, the solvent was removed by evaporation. 1000 mL Ethyl acetate was added, and the reaction mixture was extracted using DI water (3×750 mL). The combined organic layer was dried over magnesium sulfate. After filtration, the solvent was removed by evaporation. The product (27.8 g) was obtained, and was carried on to next reaction without further purification. The structure was confirmed by NMR.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:8]=[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][NH:10]1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1ccc(=O)[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Methyl 6-(4-methoxybenzyloxy)nicotinate (2.66 g, 9.73 mmol) obtained in Step 2 and anisole (10.6 mL) were dissolved in trifluoroacetic acid (15 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and saturated sodium hydrogencarbonate was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The precipitated solid was collected by filtration to afford methyl 2-oxo-1,2-dihydropyridine-5-carboxylate (1.33 g, 89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[H-].[Na+].Cl.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:16]=[CH:15][CH:14]=[C:13]2[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1)#[N:24]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3cccc(O)c3)c2cc1C#N
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
1,3-Dihydroxybenzene (110 mg, 1 mmol) was added to a stirred suspension of sodium hydride (60 mg, 2 mmol) in DMF (10 ml) and the mixture was stirred for 30 minutes. 4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg 1 mmol), (prepared as described for the starting material in Example 1), was added and the mixture was heated at 100° C. for 4 hours. The mixture was allowed to cool, was quenched with water and extracted with ethyl acetate (2×75 ml). The extracts were combined, washed with water (×2) and then brine and dried (MgSO4). The solvent was removed by evaporation and the residue was triturated with ethyl acetate/hexane, collected by filtration and dried to give 6-cyano-4-(3-hydroxyphenoxy)-7-(2-methoxyethoxy)quinoline (115 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1cc(OC)c([N+](=O)[O-])cc1OC
Solvent: CCO
Product: CCOC(=O)C(=O)N(c1ccccc1)c1cc(OC)c(N)cc1OC
Yield: 94.2 %

Procedure:
A mixture of the nitro compound of Example 2A (30 g) and 3.6 g of 5% pd/c in 600 ml of ethanol was hydrogenated at 40 psi overnight. The reaction mixture was filtered and the catalyst was washed well with methylene chloride. The organic solution was evaporated to dryness to give 26 g of the title compound. This was used for the next reaction without further purification.
Reaction SMILES: C(N(CC)[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.[F:22][C:23]([F:27])([F:26])[C:24]#[N:25]>C1COCC1>[CH3:12][O:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4]([OH:14])=[N:25][C:24]([C:23]([F:27])([F:26])[F:22])=[CH:13]2
Reactant: N#CC(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (40 mL) was added tert-butyllithium (3.99 mL, 6.78 mmol) dropwise at −78° C. After stirring for 0.5 h, 2,2,2-trifluoroacetonitrile (0.472 g, 4.97 mmol) was bubbled through the solution via syringe for 1 minute, then warmed to rt, and stirred for 16 h. The reaction mixture was quenched with water (1 mL) and partially evaporated to half to one third of original volume, neutralized with 1 N HCl. The solution was separated with EtOAc. The organics were collected, washed with brine, dried over MgSO4, filtered and evaporated to give crude material as a dark yellow solid. The crude material was purified via silica gel chromatography (90 g column, 10-50% EtOAc:Hex) to give the product 6-methoxy-3-(trifluoromethyl)isoquinolin-1-ol (271 mg, 1.114 mmol, 24.66% yield) as a light yellow solid. MS: MS m/z 244.19(M++1).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CS[C:9]1[S:10][CH2:11][CH2:12][N:13]=1.C[O-].[Na+]>C(O)C>[OH:2][CH:3]1[CH2:6][N:5]([C:9]2[S:10][CH2:11][CH2:12][N:13]=2)[CH2:4]1
Reactant: OC1CNC1
Reactant: CSC1=NCCS1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: OC1CN(C2=NCCS2)C1
Yield: 75.6 %

Procedure:
To a solution of 109 mg of 3-hydroxyazetidine HCl [Compound (15)] in 5 ml of ethanol was added a mixture of 133 mg of 2-methylthiothiazoline [Compound (16)] and sodium methoxide (0.9 equivalent mole), and the reaction mixture was refluxed for 8 hours. After removal of the solvent under reduced pressure, the resulting residue was dissolved in chloroform and washed with saturated saline solution. After removal of the solvent under reduced pressure, the resulting residue was washed with diethylether to give 119 mg (81.5%) of 3-hydroxy-1-(thiazolin-2-yl)azetidine [Compound (17)] as crystals.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:45])[CH2:42][CH2:43][CH3:44])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([C:41](=[O:45])[CH2:42][CH2:43][CH3:44])=[C:36]2[OH:38]
Reactant: CCCC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 187.9 %

Procedure:
To Dowtherm (82 mL) at 250° C. was added ethyl 2-(((4-bromophenyl)amino)methylene)-3-oxohexanoate (700 mg, 6.75 mmol) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, and the precipitate was filtered and rinsed with hexanes to afford the desired product (3.73 g, 53%) as a light brown solid. ESI MS m/z 294 [C13H12BrNO2+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19](O)=[O:20].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ncccn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ncccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.7 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with pyrimidine-2-carboxylic acid (129 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 48 hour, and then water (10 mL) was added. The reaction was stirred for 1 hour. The solid which separated was filtered and washed with CH2Cl2 (10 mL). The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide (110 mg, 38% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.21 (br s, 1H), 10.47 (s, 1H), 9.06 (d, 2H), 8.40 (d, 1H), 7 87 (d, 1H), 7.77 (t, 1H); LCMS (APCI+) m/z 335.9, 337.9 (M+H)+, Retention time=2.70 minutes (Method 2).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@@:6]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32](S(C)=O)[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1.C(N(C(C)C)C(C)C)C.O>C1COCC1>[Si:11]([O:10][C@:6]1([CH3:9])[CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:30]2[C:31]([F:37])=[CH:32][N:33]=[C:28]([C:27]3[C:21]4[C:22](=[N:23][CH:24]=[C:19]([Cl:18])[CH:20]=4)[N:25]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:26]=3)[N:29]=2)[C@H:7]1[OH:8])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H](N)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](C)(O[Si](C)(C)C(C)(C)C)[C@@H]4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of (1R,2R,6S)-6-amino-2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-cyclohexanol, 50e, (0.16 g, 0.62 mmol) in THF (8 mL) in a microwave sealed tube vessel was added 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (0.29 g, 0.63 mmol) followed by N-ethyl-N-isopropyl-propan-2-amine (0.13 mL, 0.74 mmol). The resulting reaction mixture was capped and warmed to 70° C., stirred for 14 h. The reaction mixture was cooled to ambient temperature, added water (2 mL), concentrated under reduced pressure to remove THF. The crude product was diluted with ethyl acetate (25 mL), insoluble material (sulfone 1a) was removed by filtration. The organic layer was separated, washed with brine (2×5 mL), dried over Na2SO4, filter and concentrated under reduced pressure. The crude product was purified by silica-gel plug using 10-30% ethyl acetate in hexanes as eluant to afford 350 mg of (1R,2R,6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol (50f).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]1[C@@H:18]2[C@@H:14]([NH:15][C:16](=[O:19])[NH:17]2)[CH2:13][S:12]1.FC(F)(F)C(O)=O.NCCCNC(=O)CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1.CCN(C(C)C)C(C)C.[Cl:57][C:58]1[C:63]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[N:62][N:61]=[C:60]2[N:70]([CH2:79][C:80](O)=[O:81])[N:71]=[C:72]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:59]=12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[Cl:57][C:58]1[C:63]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)=[N:62][N:61]=[C:60]2[N:70]([CH2:79][C:80]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]3[CH:18]4[CH:14]([NH:15][C:16](=[O:19])[NH:17]4)[CH2:13][S:12]3)=[O:81])[N:71]=[C:72]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:59]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC[C@@H]1SCC2NC(=O)NC21)NCCCNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-aminopropyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (also known as N-(3-Aminopropyl)biotinamide trifluoroacetate, commercially available from Sigma-Aldrich or J&K Scientific Ltd) (0.22 mmol) in anhydrous DMF (1.1 mL) were sequentially added DIPEA (57 μL, 0.33 mmol), 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (80 mg, 0.22 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, commercially available from Sigma-Aldrich or Novabiochem) (125 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate and washed with aqueous NaHCO3 and 4% aqueous LiCl. The organic phase was then dried over MgSO4, and evaporated under vacuum. The residue was purified by preparative HPLC yielding Compound 44 as a beige solid (34 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1)(=[O:21])[CH3:20]
Reactant: O=C(NCc1nccnc1Cl)[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 25 °C

Procedure:
The total harvest of (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (10 mmol, 2.7 g) and 4-dimethylaminopyridine (1.0 mmol, 0.12 g) were dissolved in pyridine (25 ml), acetic anhydride (10.51 mmol, 0.994 ml) was added and the mixture was stirred at room temperature. After 1 hour the reaction was quenched in 185 mL of 2N hydrochloric acid (pH becomes four) and extracted with ethyl acetate three times. The combined organic layers were dried (sodium sulfate) and concentrated to give 2.8 g of (trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:26])[C:10]2[CH:15]=[N:14][C:13]([C:16](OC)=[O:17])=[C:12]3[O:20]C(C)(C)[O:22][CH2:23][C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][OH:28].CC#N.CCCCCC>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:26])[C:10]2[C:11]([CH2:23][OH:22])=[C:12]([OH:20])[C:13]([C:16]([NH:27][OH:28])=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ncc([C@H](O)c2ccc(F)c(Cl)c2)c2c1OC(C)(C)OC2
Reactant: NO
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(NO)c1ncc([C@H](O)c2ccc(F)c(Cl)c2)c(CO)c1O
Reaction time: 0.5 h

Procedure:
The crude product from step 1 g, (R)-methyl 5-((3-Chloro-4-fluorophenyl)(hydroxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate, was dissolved in 4 mL of pyridine and 1.5 mL of 50% hydroxylamine in water producing a clear yellow solution that was then heated to 80° C. for 1 h (complete conversion). The aqueous pyridine was then evacuated by vacuum distillation and the residual oil dissolved in EtAc. Extraction with 10% citric acid removed residual pyridine and hydroxylamine. The organic phase became cloudy as deprotection of the acetonide was initiated. The EtAc was removed and the residual oil dissolved in 3 mL 70% formic acid. This solution was left to rest at RT for 30 min upon which completion of the deprotection was noted. The oil was then diluted with 20 mL of water and 70 mL of EtAc and the product was extracted into the organic phase. A black aqueous layer formed and was extracted with one 50 mL portion of EtAc. Following this extraction the organic phase was concentrated (to 20 mL) and extracted with 0.1N NaOH (2×20 mL). The aqueous layer was then removed and washed with hexane. The aqueous layer was again removed and acidified until complete precipitation of the product (acid pH) was observed. The precipitate was then extracted into EtAc and the aqueous layer back extracted. Evaporation of the solvent gave a foam product. MeCN (1 mL) was added to dissolve followed by hexane producing a biphasic mixture. Stirring for 30 min gave a crystalline powder precipitate which was filtered off yielding 0.56 g off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl.OS(O)(=O)=O>[Cl-].[Cl-].[Zn+2].O>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][C:14]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
2-Chlorobenzoyl chloride (177 mL, 1.4 mol) was cooled in a 2-L flask equipped with a condenser and a thermometer to 0° C. with an ice-water bath and 4-bromoaniline (100 g, 0.58 mol) was added to the cooled solution. The mixture was heated to 120° C. and kept at this temperature for 1 h until analysis by TLC indicated 4-bromoaniline had been consumed (EtOAc:hexane, 1:4). The solution was heated to 160° C. and anhydrous ZnCl2 (95 g, 0.70 mol, flamed dried) was added in one portion. The temperature was increased to 195° C. and stirring was maintained at this temperature for 3 hr until no more bubbles were evolved. The mixture was cooled to 120° C. and aq HCl (12%, 350 mL) was added dropwise slowly. The mixture was kept at reflux for 20 min, after which the aq layer was poured off. This procedure with aq HCl was repeated 4 times. Water (350 mL) was then added, and the mixture held at reflux for 20 min and then the water was poured off. This was repeated several times until the solid was not a block any more. Then H2SO4 (72%, 700 mL) was added to the residue and the mixture was heated to reflux for about 1 hr until the reaction mixture became a homogeneous dark colored solution. The hot acidic solution was poured into a mixture of ice and water with stirring. The precipitate which resulted was filtered and washed with a large amount of cold water until the pH value of the solid was about 6. The solid was then suspended in ice water and aq NaOH (40%, 290 mL) was added carefully. The mixture which-resulted was stirred for 2 hrs. The solid was filtered and washed with ice water. The suspension of the solid in ice water was adjusted carefully to approximately pH=3 with aq H2SO4 (40%) dropwise. The solid which remained was filtered and washed with water to neutrality. The yellow solid 19 (66.1 g, 37.0%) was dried and used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 6.49 (s, br, 2H), 6.65 (d, 1H, J=8.82 Hz), 7.26-7.8 (m, 6H).
Reaction SMILES: S(F)(OC)(=O)=O.[F:7][C:8]([F:25])([F:24])[C-:9]([C:20]([F:23])([F:22])[F:21])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].[CH3:26]N([S+](N(C)C)N(C)C)C.FC(F)(F)C(C(F)(F)F)=C(F)C(F)(F)C(F)(F)F>C(#N)C1C=CC=CC=1>[F:18][C:10]([F:19])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:9]([C:20]([F:21])([F:22])[F:23])([C:8]([F:24])([F:25])[F:7])[CH3:26]
Reactant: CN(C)[S+](N(C)C)N(C)C
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Agent: COS(=O)(=O)F
Agent: FC(=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: N#Cc1ccccc1
Product: CC(C(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 60 %

Procedure:
Methyl fluorosulfate (7.6 g, 0.0665 mol) was added dropwise at 0° to a stirred solution of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide, prepared by dissolving 20.2 g (0.073 mol) of tris(dimethylamino)sulfonium difluorotrimethylsilicate and 20.0 g (0.0665 mol) of 1,1,1,3,4,4,5,5,5-nonafluoro-2-trifluoromethyl-2-pentene in 75 mL of benzonitrile. The reaction mixture was warmed at 25°, and the most volatile portion of the reaction mixture was distilled out under reduced pressure. The distillate was redistilled at atmospheric pressure to give 13.27 g (60%) of 3,3,4,4,5,5,5-heptafluoro-2,2-bis(trifluoromethyl)pentane as a colorless liquid: b.p. 88°-89°; 19F NMR (CCl3F) δ -67.7 ppm (t,t 6F), -81.1 ppm (t, 3F), -110.5 ppm (m, 2F) and -123.7 ppm (m, 2F); 1H NMR (CCl3F) δ 1.72 ppm. Anal. Calcd. for C7H3F13 : C, 25.17; H, 0.91; F, 73.93. Found: C, 24.88; H, 0.87; F, 73.64.