Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8](I)[N:7]=3.C1(P(C2C=CC=CC=2)C2[C:37]3[O:36][C:35]4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(CC)CC)C.C[OH:67]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:35][O:36][C:37]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:16]=[CH:15][C:5]=32)[CH:9]=1)=[O:67]
Reactant: CO
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 50 °C

Procedure:
8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (6.000 g, 0.01534 mol) followed by palladium acetate (0.1722 g, 0.0007672 mol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.8879 g, 0.001534 mol) were added sequentially to a dry nitrogen-filled flask. Degassed triethylamine (180 mL, 1.3 mol) and methanol (60 mL) were added, and the reaction mixture was thoroughly purged with a carbon monoxide balloon for about 3 minutes. Two carbon monoxide balloons were fixed to the flask and the reaction was heated to 50° C. for 3 hours. The reaction was purged with nitrogen, concentrated in vacuo, and dry loaded onto silica gel. The crude was purified by flash chromatography (40-100% ethyl acetate in hexanes followed by 5-15% MeOH in DCM) to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid methyl ester (4.242 g) as a light brown solid. MS(ESI+) 323.0/325.0
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:4])=[O:3].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:13])([F:14])[F:15])(=[O:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1-Methylsulfonyl-2-trifluoromethoxybenzene (15.7 g, 65 mmol) was dissolved in concentrated sulfuric acid (27 mL) and the solution was heated to 40° C. Nitric acid (100%, 27 mL) was added dropwise over 45 minutes. The reaction mixture was allowed to stand overnight at 60° C., cooled, and then poured on crushed ice (300 mL). The precipitated product was isolated by filtration, washed with water (10×50 mL) and dried (MgSO4), affording 17.5 g of 3-methylsulfonyl-4-trifluoromethoxynitrobenzene.
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([F:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23]C)=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:9]([O:8][P:6]([CH:13]([F:27])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:25][CH:26]=1)([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(N)Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1ccc(CC(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To compound 21 (690 mg, 1.71 mmol) in dioxane (17 mL) was added 1 N NaOH (8.6 mL, 5 eq.) and it was stirred at ambient temperature (25 minutes), yielding a solution of crude 4-[bis(tert-Butoxy)phosphorylfluoromethyl]-D,L-phenylalanine (22), which was not isolated. The pH was adjusted to 8 by bubbling in CO2 gas, Fmoc-OBT (673 mg, 1.88 mmol) was added and the mixture stirred at ambient temperature (3 hours). Ice-cold 5% citric acid (30 mL) was added and the resultant solution was extracted with CHCl3 (3×30 mL). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to yield crude 23 (1.48 g). Purification by silica gel chromatography afforded pure 23 as a colorless foam (407 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)C2CCNCC2)cc1
Reactant: COc1ccc(OCCCCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(C(c2ccc(OC)cc2)C2CCN(CCCOc3ccc(OC)c(OC)c3)CC2)cc1

Procedure:
A mixture of 5.58 g (0.02 mole) of 4-[bis(4-methoxyphenyl)methyl]piperidine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate, 5.52 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was stripped to dryness, and the residue partitioned between chloroform-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a dark brown oil. The oil was subjected to column chromatography on a silica gel column with elution via ethyl acetate-dimethoxy ethane. This produced 4.72 g (46.7%) of dark brown oil.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][CH2:8][C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][CH:18]=2)[C:14]=1[Cl:15].[N+:20]([O-])([OH:22])=[O:21]>>[Cl:6][CH2:7][CH2:8][C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[N+:20]([O-:22])=[O:21])[C:14]=1[Cl:15]
Reactant: O=[N+]([O-])O
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnn2c(Cl)c(CCCl)c(Cl)nc12
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 100 ml of concentrated sulfuric acid cooled to 0° C with ice water, were added 50 ml of 90% nitric acid gradually so as not to raise the temperature. After the resultant mixed acid was stirred for a while, 13.80 g of the compound prepared in Example 49 as remained crystals were added gradually so as not to raise the temperature also. The resultant mixture was stirred for 4 hours while maintaining the temperature at 0° C. Since spots attributable to the raw materials on TLC disappeared, the stirring was stopped, and the reaction mixture was poured into ice water. Crystals deposited were collected by filtration and air-dried to obtain 15.61 g (yield: 95.5%) of the intended product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]2[NH:17][C:18](=[O:23])[O:19][C:20]([CH3:22])([CH3:21])[C:15]=2[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([C:31]#[N:30])=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]2[NH:17][C:18](=[O:23])[O:19][C:20]([CH3:22])([CH3:21])[C:15]=2[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (2.0 g, 5.8 mmol) in THF (anhydrous, 50 mL) at −78° C. was added chlorosulfonyl isocyanate (0.66 mL, 6.7 mmol). After 90 min. DMF (9 mL, 116 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.1 g, 52%) as a white powder, mp 165–167° C. 1H NMR (d6-DMSO, 300 MHz) δ 1.36 (s, 9H), 1.61 (s, 6H), 6.44 (d, 1H, J=3.7 Hz), 6.92 (d, 1H, J=8.2 Hz), 7.27–7.32 (m, 2H), 7.36 (‘d’, 1H, J=1.5 Hz), 10.36 (s, 1H). MS (EI) m/z 367 [M]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:32][CH2:31][CH2:30][CH2:29][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)=[O:8].C(N(CC)CC)C.[Cl:40][S:41]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](Cl)=[O:48])(=[O:43])=[O:42]>ClCCl>[Cl:40][S:41]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([NH:1][C:2]1[S:3][C:4]2[CH2:32][CH2:31][CH2:30][CH2:29][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[CH:14][CH:15]=1)=[O:8])=[O:48])(=[O:43])=[O:42]
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 29.3 %

Procedure:
To a mixture of 3.34 g of methyl 4-[3-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)propyl]benzoate, 2.2 mL of triethylamine, and 40 mL of dichloromethane were added a mixture of 2.2 g of 3-(chlorosulfonyl)benzoyl chloride and 10 mL of dichloromethane under ice-cooling, followed by stirring at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was suspended in ethanol. The precipitate was collected by filtration to obtain 1.42 g of methyl 4-[3-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)propyl]benzoate as a yellow solid.
Reaction SMILES: C1C=CC(C(NC(C(N[C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=O)CCCN=C(N)N)=O)=CC=1.Cl.CS(C)=[O:33]>Cl>[CH:23]1[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:21]([OH:33])[CH:22]=1
Reactant: CS(C)=O
Reactant: NC(N)=NCCCC(NC(=O)c1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 5.5 h

Procedure:
Substrate stock solutions were prepared by dissolving ˜50 mg BAPNA or suc-AAPF-PNP in DMSO; these stock solutions were then diluted with DMSO and 0.1 M TRIS/HCl buffer (pH 7.4) to provide substrate solutions of various concentrations (final concentration of DMSO in each substrate solution was 15% v/v). A measured quantity of particles, 30-100 mg, were placed in a microcentrifuge tube, 1.3 ml of substrate solution was added, and the mixture was bath-sonicated to completely disperse the particles. The mixture was then placed in a water bath at 30° C. for 5-6 hours, with additional agitation provided every 45-60 minutes. The mixture was then removed from the water bath and centrifuged at 14,000 rpm for 30 minutes. The reaction time was measured from initial sonication to the beginning of centrifugation. Catalytic activity was determined from the increase in free p-nitrophenol concentration, measured by UV/VIS spectroscopy at 410 nm with an extinction coefficient of 8500 M−1 cm−1. The measured absorbance was compared to that of the substrate solution at 410 nm and from the absorbance due to light scattering of the particle dispersion of particles in 0.1 M Tris buffer (prepared identically as above) at 410 nm. These contributions to the absorbance were subtracted from the total absorbance at 41 0 nm to obtain the absorbance due to free p-nitrophenol. Each data point was calculated based on the average of 3 to 7 trials.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][C:11]([CH3:13])([CH3:10])[O:5][CH2:4]1
Reactant: CC(C)=O
Reactant: OCC(CO)(CBr)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCC(CBr)(CBr)CO1

Procedure:
A mixture of 10 g of 2,2-bis(bromomethyl)-1,3-propanediol, 5 ml of acetone and a catalytic quantity (0.1 g) of p-toluenesulfonic acid was heated under reflux in 150 ml of benzene until the theoretical amount of water (0.8 ml) had been collected in a Dean-Stark trap (2 hours). Evaporation of the solvent gave 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (6A), as a solid, m.p.: 56°-58° C. The purity according to gas-liquid chromatography and proton NMR was 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:12]=[C:11]([CH:26]=O)[C:10]=2[OH:28])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>>[ClH:1].[C:29]([NH:33][CH2:26][C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[OH:28])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=Cc1cc(CCCCc2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(CCCCc2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
3-((tert-Butylamino)methyl)-3′,4′-dichloro-5-(4-(4-chlorophenyl)butyl)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 3′,4′-dichloro-5-(4-(4-chlorophenyl)butyl)-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: Br[C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][Br:7].C(NC1C=C(OC)C=CC=1Cl)(=O)C.[C:22]([NH:25][C:26]1[CH:31]=[C:30]([O:32]C)[CH:29]=[CH:28][C:27]=1[Br:34])(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[C:27]([Br:34])=[CH:28][C:29]([C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][Br:7])=[C:30]([OH:32])[CH:31]=1)(=[O:24])[CH3:23]
Reactant: O=C(Br)CCCCBr
Reactant: COc1ccc(Br)c(NC(C)=O)c1
Agent: COc1ccc(Cl)c(NC(C)=O)c1
Product: CC(=O)Nc1cc(O)c(C(=O)CCCCBr)cc1Br

Procedure:
Proceeding as in Example 4, Step (a), but replacing 1,5-dichlcoro-pentan-1-one with 1,5-dibromopentan-1-one and N-acetyl-2-chloro-5-methoxyaniline with N-acetyl-2-bromo-5-methoxyaniline, gave 1-(4-acetylamino-5-bromo-2-hydroxyphenyl)-5-bromopentan-1-one.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14]COC)([CH2:12][F:13])[CH2:10][F:11].[Li]CCCC.[B:23](OC(C)C)(OC(C)C)[O:24]C(C)C>C1COCC1>[F:11][CH2:10][C:9]1([CH2:12][F:13])[O:14][B:23]([OH:24])[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]1=2
Reactant: COCOC(CF)(CF)c1ccc(C)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)B(O)OC2(CF)CF
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 2-bromo-1-(1,3-difluoro-2-(methoxymethoxy)propan-2-yl)-4-methylbenzene (1.2 g, 3.9 mmol) in THF (20 mL) at −78° C. was added n-BuLi (4 mL, 9.75 mmol) dropwise. The mixture was stirred at −78° C. for additional 1 h and then triisopropyl borate (1.5 g, 7.9 mmol) in 10 mL of THF was added below −70° C. The resulting mixture was kept stirring at −78° C. for 30 min and allowed to warm to rt and stirred overnight. Then it was quenched with aqueous NH4Cl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on column chromatography to provide the product (0.5 g, yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][NH:13][CH:12]([CH3:17])[C:11]=3[N:10]=C2)=[N:6][CH:7]=1.[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)[N:33]=[N:10][C:11]=2[CH:12]1[CH3:17])=[O:22]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1NCCc2c1ncn2-c1ncc(F)cn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1c2nnn(-c3ncc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Yield: 90.4 %

Procedure:
A solution of 1-(5-fluoropyrimidin-2-yl)-4-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (0.30 g, 1.28 mmol), 2-chloro-3-(trifluoromethyl)benzoic acid (0.34 g, 1.54 mmol), HATU (0.38 g, 1.28 mmol), and Et3N (0.18 mL, 1.28 mmol) in DMF (5 mL) was stirred for 30 min. The reaction was diluted with EtOAc (30 mL) and washed with H2O (3×20 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.51 g, 90%). 1H NMR (500 MHz, CDCl3) δ 8.80-8.43 (m, 2H), 7.82-7.44 (m, 1H), 7.27-7.15 (m, 2H), 6.66-6.60 (m, 1H), 5.95-4.92 (m, 1H), 3.77-2.54 (m, 3H), 1.74-1.53 (m, 3H). MS (ESI): mass calculated for C18H13ClF4N6O, 440.08. m/z found, 441.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:11]([NH:16][NH2:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(Cl)c(NN)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2,3-Dichloro-6-methoxyquinoxaline (4.2 g., 0.018 mole), the product of Preparation E(b), and 2.7 ml. of hydrazine hydrate in 100 ml. of ethanol were heated under reflux for 4 hours and stirred at room temperature overnight. The precipitate was removed by filtration and washed with ethanol to afford 3.9 g. (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline, m.p. <250° C. Mass spectrum: m/e, 224 (P); m/e 226 (P+2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:35]([O:37][CH3:38])=[O:36])[CH2:9]2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3CCCN(C(=O)OC)C3)cnc2N)cc1F
Reaction time: 0.5 h

Procedure:
To methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (55 mg, 0.166 mmol) (for synthesis, see Example 34, Step 7) in DCM (3 mL) in ice bath was added DIEA (0.116 mL, 0.666 mmol) and methyl chloroformate (0.013 mL, 0.166 mmol). The reaction mixture was stirred at in ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue (50 mg, 77%) was taken to the next step without further purification. LCMS (m/z): 389.2 (MH+), 0.785 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:6][C:5]4[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Fc1ccc(CCl)c(C(F)(F)F)c1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 4-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (38% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.04, 7.81, 7.36, 7.20-7.29, 6.96, 3.76, 3.68, 3.56, 2.61, 1.51, 0.68-0.84, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][N:27]=1)[C:12]([NH:14][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1)=[O:13].[CH3:28][C:29]([CH3:58])([O:31][C:32](=[O:57])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:51]([C:50]2[CH:49]=[C:48]([CH2:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][C:32]([O:31][C:29]([CH3:58])([CH3:30])[CH3:28])=[O:57])[CH:56]=[CH:55][CH:54]=2)=[O:52])=[C:3]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[NH:14][C@@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH:25]=[CH:26][N:27]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 65 °C
Yield: 66.6 %

Procedure:
To a solution of (S)-2-(2-amino-5-chlorophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 237b (1.02 g, 2.7 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid 251c (1.19 g, 2.7 mmol), DIPEA (1.04 g, 8.1 mmol) and DMAP (190 mg, 1.55 mmol) in DMF (20 ml) was added HATU (1.13 g, 2.97 mmol). The reaction mixture was heated at 65° C. for 24 hours, then cooled and concentrated. The residue was combined with another run (0.28 mmol scale), dissolved in DCM (150 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (10% to 30% EtOAc in DCM) gave the title compound (1.44 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S-:20].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:20][CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 71.4 %

Procedure:
A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.015 g), sodium thiomethoxide (635 mg) was heated to 80° C. in dimethylformamide (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg). To a solution of 4-methylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg) in chloroform (15 mL) was added mCPBA (1.46 g). After stirring for 2 days, the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to yield 4-methanesulfonyl-piperidine-1-carboxylic acid tert-butyl ester (505 mg) as a white solid. Treatment of this compound with HCl in dichloromethane/methanol yielded 4-(methylsulfonyl)piperidine, which was isolated as the hydrochloride salt.