Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13](CO)[O:12][C:11](=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]Br.CN([CH:36]=[O:37])C>CCCCCC.CCOC(C)=O>[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH2:22][O:37][CH2:36][CH:10]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][O:12][C:11]2=[O:16])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)C(CO)O1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1OCC(c2ccc(Cl)c(Cl)c2)C1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 60 h
Yield: 71 %

Procedure:
Treat a solution of 4-(3,4-dichlorophenyl)-dihydro-5-(hydroxymethyl) 2(3H)-furanone (3.3 g, 12.6 mmol, 3:2 ratio of stereoisomers by NMR) in dry DMF(10 mL) with 3,5-bistrifluoromethylbenzyl bromide (5.9 mL, 32.2 mmol) followed by Ag2O (5.8 g, 25.3 mmol); wrap the vessel in foil and stir for 2.5 d. Apply the crude material to a pad of silica gel (10 cm×4 cm) packed with hexane:EtOAc (1:1), washing the pad with the same solvent until no further product is eluted as shown by TLC; concentrate the resulting filtrate in vacuo to give the crude product as a solid (10 g). Dissolve the crude was dissolved in hexane:EtOAc (4:1) and purify by silica gel chromatography (column: 7.5×19; solvent: hexane:EtOAc, 4:1) to give 3.33 g (6.8 mmol, 54%) of isomer (trans)-[[[(3,5-bis(trifluoromethyl)phenyl]methoxy]methyl]-4-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone and 1.08 g (2.2 mmol, 17%) of the corresponding cis isomer for a total yield of 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:68][CH2:69][CH2:70][CH2:71][CH:72]2[CH2:76][CH2:75][NH:74][CH2:73]2)[CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH:72]([CH2:71][CH2:70][CH2:69][CH2:68][N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)[CH2:73]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C(CCN1CCCC1)CC1CCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(CCCCN4CCCC4)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-[4-(pyrrolidin-1-yl)-butyl]-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.O.O[N:26]1[C:30]2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[CH3:30][NH:26][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 70 h
Yield: 84 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-tyrosine (300 g, 1.07 mol) in DMF (2 L) were successively added methylamine hydrochloride (86.4 g, 1.28 mol), 1-hydroxybenzotriazole monohydrate (163 g, 1.07 mol, hereinafter to be abbreviated as HOBt.H2O), N-methylmorpholine (258 mL, 2.35 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245 g, 1.28 mol, hereinafter to be abbreviated as WSCI.HCl), under ice-cooling (internal temperature 10° C.). The reaction mixture was stirred for 70 hr while gradually raising the temperature to room temperature. The reaction mixture was poured into iced water (10 L), and the precipitate was collected by filtration and washed with water and ether. The obtained precipitate was recrystallized from ethyl acetate (7 L) to give the title compound (265 g, 84%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]#[C:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:24]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:35][I:36]>C(Cl)Cl>[I-:36].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]#[C:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:19])[CH2:3][N+:2]([CH3:35])([CH3:1])[CH3:34])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CI
Reactant: Cc1cccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)c1
Solvent: ClCCl
Product: Cc1cccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)C[N+](C)(C)C)s2)c1
Product: [I-]

Procedure:
To a solution of (R)-benzyl 4-(dimethylamino)-3-(5-(m-tolylethynyl)thiophene-2-sulfonamido)butanoate (25 mg, 0.05 mmol) and methyl iodide (100 μL, 40 eq) in CH2Cl2 (1 mL) was stirred overnight at room temperature. The solution was concentrated to give the title compound in quantitative yield. MS ESI 511.3 [M]+, calcd for [C27H31N2O4S2]+ 511.17.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][C:31]([CH3:33])=[O:32]>>[CH:27]([OH:26])=[O:32].[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:31]([CH3:33])[CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)C)C3)cc1
Product: O=CO

Procedure:
Method as example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2 yl)phenyl)urea (example 13) and acetone as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([OH:14])[N:8]=[CH:9]2)([O-:3])=[O:2].[C:15](O)(=[O:17])[CH3:16].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:15]([O:14][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)(=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1cccc2cnc(O)cc12
Reactant: CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 120 °C

Procedure:
5-Nitro-3-isoquinolinol (3.40 g, 17.9 mmol) in acetic anhydride (40 mL) was treated with acetic acid (5 mL) and pyridine (5 mL) and heated at 120° C. for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. MS (ESI+) m/z 233 (M+H)+; MS (ESI−) m/z 231 (M−H)−; 1H NMR (DMSO, 300 MHz) isomers δ 2.39 (s, 3H), 7.88 (m, 1H), 8.27 (m, 1H), 8.50 (m, 1H), 8.65, 8.74 (d, J 7.8, 1H), 9.47, 9.55 (s, 1H).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:6])[CH3:5].[OH-].[K+].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[C:12]([Cl:18])[CH:11]=1>O1CCCC1.C(OCC)C.C1OCCOCCOCCOCCOCCOC1>[Cl:18][C:12]1[CH:11]=[C:10]([F:9])[CH:17]=[CH:16][C:13]=1[CH2:14][N:3]([O:2][CH3:1])[C:4](=[O:6])[CH3:5]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CONC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON(Cc1ccc(F)cc1Cl)C(C)=O
Temperature: 25 °C
Yield: 33.5 %

Procedure:
To a stirred mixture of 1.95 g (0.0219 mole) of N-methoxyacetamide, 1.23 g 0.022 mole) of powdered potassium hydroxide, and a small amount (~0.05 g) of 18-crown-6 in 10 ml of tetrahydrofuran was added a solution of 5.05 g (0.0226 mole) of 4-fluoro-2-chlorobenzyl bromide in 15 ml of tetrahydrofuran. This mixture was heated at reflux for approximately 17 hours and then was allowed to cool to room temperature. The mixture was diluted with 125 ml of diethyl ether and was washed with an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a yellow oil. This oil was purified by column chromatography on silica gel, eluting with ethyl acetate:n-heptane (25:75) followed by ethyl acetate:n-heptane (50:50) , to yield 1.7 g of N-(2-chloro-4-fluoro-benzyl)-N-methoxyacetamide as an oil.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]([CH3:13])=[C:11]([Cl:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]1)=[O:7])(C)(C)C.Cl.O1CCOCC1.CCOCC>ClCCl>[Cl:14][C:11]1[C:10]([C:15]([F:17])([F:16])[F:18])=[N:9][N:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH3:13]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)O
Reaction time: 2 h

Procedure:
To a stirred solution of 43.62 mmol of 4-chloro-5-methyl -3-trifluoromethyl pyrazole-1-carboxylic acid tertbutyl ester in 20 mL of dichloromethane, carefully add 40 mL of 4M HCl/dioxane. The reaction mixture was allowed to stir for 2 hours. Add fresh ether and filter the white solid obtained. Vaccum dry to give the title compound 4-chloro-5-methyl -3-trifluoromethyl pyrazole-1-carboxylic acid in 96% yield. LC-MS ink=242 (M+)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:15][CH:16]([O:22]CC)[C:17](OCC)=O)C>C[N+]([O-])=O>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:17]([C:16]([O:15][CH3:13])=[O:22])[O:10][CH2:9][CH2:8]2
Reactant: CCOC(=O)C(OCC)OCC
Reactant: COc1c(Br)cccc1CCO
Solvent: C[N+](=O)[O-]
Product: COC(=O)C1OCCc2c1ccc(Br)c2OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(3-bromo-2-methoxyphenypethanol To a solution of methyl (3-bromo-2-methoxyphenyl)acetate (8.2 g, 31.66 mmol) in 200 mL of dry THF under N2 at room temperature was added LiBH4 (32 mL, 63.32 mmol, 2M THF). After 1.5 hours, the reaction was warmed to reflux for 3 hours, and then cooled to room temperature. The solution was poured into EtOAc/1N HCl solution, and the layers were separated. The organic layer was washed with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 2-(3-bromo-2-methoxyphenyl)ethanol. Step E: methyl 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylate TiCl4 (9.84 g, 104 mmol) was added over a period of 20 min to an ice-cooled mixture of 2-(3-bromo-2-methoxyphenyl)ethanol (6 g, 26.0 mmol) and ethyl diethoxyacetate (5.5 g, 31.1 mmol) in 60 mL of CH3NO2. After stirred for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatograph to give methyl 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: [O:1]=[C:2]([O-:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Na+].[OH-].[Na+].[Fe:17](Cl)Cl>O>[Fe:17].[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[C:2]([O-:13])=[O:1]
Reactant: Cl[Fe]Cl
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)C(O)C(O)C(O)CO
Product: [Fe]

Procedure:
A 1.0 M catalyst (referred to in Table 6 below as VTH) can be prepared as follows: (1) Add 218 grams (1.0 M) of technical grade sodium gluconate (2,3,4,5,6-pentahydroxycaproic acid sodium salt) to 700 milliliters of de-chlorinated tap water or equivalent. Mix solution to completely dissolve the sodium gluconate. (2) Add 59 milliliters of 50% sodium hydroxide to the mixture and continue to mix. (3) Slowly add 113 milliliters of 38-40% iron chloride solution to the solution while monitoring pH with continued mixing to form iron-2,3,4,5,6 pentahydroxyhexanoate. The pH of the final solution should be circum-neutral (6.5-7.5). Adjustments back into the circum-neutral range can be made with caustic soda (if below 6.5) or with ferric chloride (if above 7.5).
Reaction SMILES: N1([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])C2C=CC=CC=2N=N1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1.CCN(CC)CC>C1COCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])([CH3:13])[NH:24]2)=[N:21][CH:22]=1
Reactant: CC(C)=CC(=O)n1nnc2ccccc21
Reactant: NNc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(Br)cn2)N1
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
(400 mg, 2.0 mmol) 1-Benzotriazol-1-yl-3-methyl-but-2-en-1-one (Example 1, step 1), (5-bromo-pyridin-2-yl)-hydrazine (410 mg, 2.2 mmol, 1.1 equiv.) and Et3N (1.95 ml, 14.0 mmol, 7 equiv.) were dissolved together in THF (2 ml) and stirred for 90 minutes at reflux temperature. The reaction mixture was cooled and extracted with saturated Na2CO3 solution and two times with ethyl acetate. The organic extracts were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 2-(5-bromo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (230 mg, 43% yield) was obtained as a yellow oil, MS: m/e=270.2/272.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>C(OCCO)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:10]=1
Reactant: CCCCCCBr
Reactant: COc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCO
Product: CCCCCCOc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(OC)cc3)n2)c(O)c1
Reaction time: 12 h

Procedure:
15.2 g (0.038 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis(4-methoxyphenyl)-1,3,5-triazine of the formula (108b), 5.2 g of potassium carbonate and 50 mg of potassium iodide are heated at 110 C. in 100 ml of 2-ethoxyethanol for 45 minutes, and then 6.9 g (0.042 mol) of 1-bromohexane are added dropwise over the course of 15 minutes. The mixture is stirred at 110 C. for 12 hours, cooled to 0 C. and filtered. The solid material is washed neutral with water, then washed with methanol and dried. Recrystallization from 2-ethoxyethanol gives the pure, light-yellow product of the formula ##STR23##
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:31]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:31])=[C:7]2[CH:6]=[N:5]1)=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1ccc(Nc2ccnn2C(C)C)c(C(=O)O)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCN(CC)S(=O)(=O)c1ccc2nc3c(cnn3C(C)C)c(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl)-5-(diethylaminosulfonyl) anthranilic acid (12.0 g, 0.031 mol) and POCl3 (80 ml) is refluxed for 6 hours. The reaction mixture is cooled to room temperature, and then is poured into ice water and neutralized with concentrated NH4OH. The mixture is extracted with CH2Cl2 and the CH2Cl2 layer is dried over MgSO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 10 g of crude 1-isopropyl-6-(diethylaminosulfonyl)-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:9][NH2:10]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNc1ccc(Br)cn1
Reaction time: 2 h

Procedure:
To 5-bromo-2-fluoropyridine (3-1) (46 g, 261 mmol) in THF (460 mL) was added hydrazine (41.9 g, 41.0 mL, 1.31 mol). The mixture was heated to reflux and stirred vigorously for 2 h. After cooling, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (3-2) was used in the subsequent step without further purification. LC/MS: m/z (M+H)=187.9.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:36][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:34][CH3:35])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 82.7 %

Procedure:
A mixture of (N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 104, 360 mg, 0.74 mmol), iron (247 mg, 4.43 mmol) and NH4Cl (27.6 mg, 0.52 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2 h. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (280 mg, 83%) as a beige foam; 1H NMR: 1.69-1.83 (1H, m), 1.97-2.10 (1H, m), 2.18 (6H, s), 2.78-2.87 (1H, m), 2.88-2.98 (2H, m), 3.11 (1H, dd), 3.15-3.22 (1H, m), 3.74 (3H, s), 3.87 (3H, s), 4.29 (2H, br s), 6.70 (1H, s), 7.1-7.19 (2H, m), 7.21-7.28 (1H, m), 7.46 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.25 (1H, d), 8.29 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 458.35.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)(O)[O-].[Na+].O1[CH2:22][CH2:21]OCC1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:22]1[CH:21]=[CH:2][CH:3]=[CH:4][N:9]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C1COCCO1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1

Procedure:
0.55 g of Tetrakis-triphenylphosphine palladium was added to a 1,4-dioxane (20 ml) solution of 2.1 g of 3-bromo-4-fluoro-nitrobenzene and 2.3 g of 2-trimethyltin-pyridine, and the reaction liquid was heated overnight under reflux. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=7/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])I.[F:15][C:16]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:17]=1[NH2:18]>CS(C)=O.[Cu]>[F:15][C:16]1[CH:22]=[C:21]([C:5]([F:8])([F:7])[C:4]([F:10])([F:9])[C:3]([F:12])([F:11])[C:2]([F:14])([F:13])[F:1])[CH:20]=[CH:19][C:17]=1[NH2:18]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]
Solvent: CS(C)=O
Product: Nc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
A dispersion of 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (3.50 9, 10.1 mmol), 2-fluoro-4-iodoaniline (2.00 g, 8.4 mmol) and copper bronze (1.93 g, 30.4 mmol) in DMSO (10 ml) was stirred at 120° C. for 15 h. Copper(I) iodide was removed by filtration through Celite®. Et2O (100 ml) was used to wash the Celite® plug. Water (100 ml) was then added to the filtrate and the mixture stirred at RT for 5 min. The organic layer was separated and washed 5× with water to remove DMSO, dried (Na2SO4) and concentrated. Flash chromatography on silica gel (10% EtOAc/Hexane) afforded 2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl) aniline (1.69 g, 61%). 1H NMR [300 MHz, CDCl3] δ 7.25-7.14 (m, 2H), 6.86-6.74 (m, 1H), 4.07 (br s, 1H). LCMS (ACPI−) 328 (100%).
Reaction SMILES: [F:1][C:2]1([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.ClC1C(C2(F)CCC3(OCCO3)CC2)=NC=CC=1>>[F:1][C:2]1([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: FC1(c2nccs2)CCC2(CC1)OCCO2
Agent: FC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Product: O=C1CCC(F)(c2nccs2)CC1

Procedure:
The title compound was prepared using the procedure as described in Example 1C, except for substituting the product of Example 20B for the product of Example 1B. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.95 (m, 2 H), 2.61-2.72 (m, 6 H), 2.24-2.42 (m, 2 H). MS (DCI) m/e 200 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:24]=[CH:23][C:22]([NH2:25])=[N:21][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].[CH2:30]([O:32]CC)[CH3:31]>FC(F)(F)C(O)=O.CO>[C:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:24]=[CH:23][C:22]([NH2:25])=[N:21][C:11]3=[N:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:30](=[O:32])[CH3:31])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2n1
Reactant: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)Oc1ccc(-c2nc3ccc(N)nc3nc2-c2ccc(OC(C)=O)cc2)cc1
Temperature: 80 °C
Yield: 79 %

Procedure:
201.0 mg (0.5 mmol) of 2,3-bis(4-hydroxyphenyl)-pyrido[2,3-b]pyrazin-6-ylamine was dissolved in 10 ml of trifluoroacetic acid. 0.355 mL (5.0 mmol, 10.0 eq) of acetyl chloride was added via syringe to this mixture. Upon heating to 80° C. bubbling of the reaction mixture and evolution of HCl gas was observed. The reaction mixture was heated at 80° C. for 1 hr, at which point LC/MS indicated a complete conversion of the starting material to the di-acetate. Solvent was removed in vacuo to give brown solid. The solid was dissolved in 3.0 mL of methanol and this solution was added to 40 mL of diethyl ether. Upon standing for about an hour a brown precipitate was formed. It was centrifuged down, washed with 45 mL of diethyl ether twice and dried in vacuo to give 191.9 mg (79.0%) of the product as a light-brown solid. 98% purity by LC/MS (230 DAD). Mass-spec [ES+]=415.5. 1H NMR (MeOH-d4) 2.28 (6H, s), 7.10–7.12 (4H, d), 7.24–7.26 (1H, d), 7.48–7.50 (2H, d), 7.54–7.56 (2H, d), 8.24–8.26 (1H, d).