Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[S:16][CH3:17].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7]([Cl:27])=[O:8])=[CH:5][C:4]=1[S:16][CH3:17]
Reactant: O=S(Cl)Cl
Reactant: COc1c(SC)cc(C(=O)O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(SC)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoic acid (277 mg), toluene (7 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.12 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:36])[CH:13]=[C:14]([O:17][CH2:18][C:19]3[N:20]([CH3:35])[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=4)[CH:23]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:36][C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[N:20]([CH3:35])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:33])([F:34])[F:32])=[CH:26][CH:25]=3)[CH:23]=2)[CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:37])=[O:5]
Reactant: Cc1cc(OCc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C)cc2c1ccn2CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(OCc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C)cc2c1ccn2CC(=O)O

Procedure:
In analogy to the procedure described for example 1 f], {4-methyl-6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {4-methyl-6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as colorless solid.
Reaction SMILES: [I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].C[N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O.N1CCCC1>C(OCC)(=O)C>[I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)c1

Procedure:
A mixture of 141 g. of 10-(1,1-dimethylethyl)-3-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 725 ml. of N-methyl-2-pyrrolidinone and 75 ml. of pyrrolidine is stirred and heated at reflux for 1 hour, then cooled and diluted with 3.6 l. of ethyl acetate. The resulting precipitate of 10-(1,1-dimethylethyl)-3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. >360° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[NH2:25][CH2:26][C:27]1[C:32]([CH2:33][CH3:34])=[N:31][C:30]2[N:35]([CH2:38][CH3:39])[N:36]=[CH:37][C:29]=2[C:28]=1[NH:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>ClCCl>[CH2:38]([N:35]1[C:30]2=[N:31][C:32]([CH2:33][CH3:34])=[C:27]([CH2:26][NH:25][C:8]([C:5]3([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)=[O:10])[C:28]([NH:40][CH:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[C:29]2[CH:37]=[N:36]1)[CH3:39]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)OC)CC1
Temperature: 0 °C

Procedure:
To 1-[(methyloxy)carbonyl]cyclopropanecarboxylic acid (7.00 g, 48.5 mmol) in a 250 mL round-bottom flask under nitrogen in dichloromethane (DCM) (75 mL) was added thionyl chloride (19.33 mL, 265 mmol) and the solution heated to reflux. After 1.5 h the solvent and excess thionyl chloride was evaporated off. The clear residue was dissolved in DCM (120 mL), cooled under nitrogen to 0° C. and then diisopropylethylamine (23.13 mL, 132 mmol) was added dropwise. This gave white fumes and a red-brown solution that was stirred in an ice bath while adding 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (15 g, 44.1 mmol) as a solid. After 15 min the icebath was removed. After 2.5 h the reaction was quenched, the mixture was partitioned between dichloromethane and saturated sodium bicarbonate and the aqueous layer extracted well with dichloromethane. The combined organics were washed with water and brine, dried (MgSO4), filtered and evaporated. This gave a dark brown oil/foam, 23.6 g, (>100%). The crude product was purified on a 330 g Companion XL silica cartridge, eluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes. Much of the dark material came straight off the column and product appeared to come off in two broad peaks that were evaporated separately. The early fractions contained the desired product 12.25 g, (65%). HPLC 1.86 min (ret time), 98.4%; LC-MS m/z 430 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:27])[N:12]=3)=[CH:9][N:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cncnc2CC2CC2)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cncnc2CC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylsulfanyl)-4,5′-bipyrimidine (4a) (62.5 mg, 0.242 mmol) in DCM (968 μl), mCPBA (65.1 mg, 0.290 mmol) was added and the reaction mixture was stirred at rt for 1 hour. The crude reaction mixture was partitioned between saturated sodium bicarbonate solution and DCM. The aqueous layer was separated and back-extracted twice with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was carried on to the next step without further purification. MS (ES+): m/z=275.2 (100) [MH+]. HPLC: tR=0.72 minute over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1>C(O)(C(F)(F)F)=O.ClCCl>[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1csc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise fuming nitric acid(90%, 8.6 mL, 183 mmol) to a mixture of 3-bromo benzo[b]thiophene (39g, 183 mmol) in TFA(100 mL) and dichloromethane (400mL) at 0° C. The reaction turn greenish, then yellow precipitates. To this reaction mixture, add dichloromethane (200 mL) and the reaction stir at 0° C. for 30 min. Then pour the reaction into ice-water (2 L). Extract with dichloromethane (3×500mL) and the organic layer dry over MgSO4. Evaporation give a yellow solid. The resulting yellow solid triturate with diethyl ether to give a yellow solid. (Total: 34.8 g, 73%). Mass spectrum (m/e): 259 (M+1); 1HNMR(300 MHz, DMSO-d6) δ ppm: 7.70 (tt, 2H), 8.04 (d, 1H), 8.17 (d, 1H). 3CNMR(75 MHz, DMSO-d6) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]([C:9]1([S:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]3)=[S:21])[C:16]([F:28])=[CH:15][C:14]=2[Cl:29])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:29][C:14]1[C:13]([S:12][C:9]2([C:7]([O:6][CH3:5])=[O:8])[CH2:10][CH2:11]2)=[CH:18][C:17]([N:19]=[C:20]2[N:22]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:1](=[O:2])[S:21]2)=[C:16]([F:28])[CH:15]=1
Reactant: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(Sc2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
While stirring at a temperature of from 0° to +10° C., 5.7 ml of a 20% solution of phosgene in toluene are added dropwise to a solution of 3.7 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclopropanecarboxylic acid methyl ester and 4.6 ml of triethylamine in 100 ml of toluene. The reaction mixture is then stirred for 4 hours and then introduced into ice-water. The organic phase is then separated off and dried over sodium sulfate. Concentration by evaporation and subsequent chromatographic purification by means of silica gel chromatography yield 3.7 g of 9-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclopropylthio)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7-one, having a melting point of +149° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
to a solution of 4-nitrophenol (75 g, 0.54 mol) in glacial acetic acid (700 ml) was added bromine (40 ml). The solution was stirred at room temperature under an atmosphere of nitrogen for 24 hours. The solvent was evaporated under reduced pressure and the residue was recrystallized from dichloromethane to give the title compound. 1H NMR (250 MHz, CDCl3) δ 8.45 (1H, d, J 2.7 Hz), 8.16 (1H, dd, J 9.0 Hz and 2.6 Hz), 7.13 (1H, d, J 9.1 Hz), and 6.18 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:25]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:24])[N:15]1[CH2:14][CH2:13][CH2:12][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(O)cccc1F
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCCCN1C(=O)c2ccccc2C1=O
Yield: 94.8 %

Procedure:
2-fluoro-6-hydroxybenzonitrile (411 mg, 3 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (885 mg, 3.3 mmol), and potassium carbonate (1.24 g, 9 mmol) were heated overnight at 70° C. in N,N-dimethylformamide (6 mL). The mixture was cooled, diluted with water, and the precipitate filtered and dried to give 922 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.79-7.87 (m, 4H), 7.69 (td, J=8.6, 6.9 Hz, 1H), 7.01-7.07 (m, 2H), 4.22 (t, J=5.8 Hz, 2H), 3.79 (t, J=6.6 Hz, 2H), 2.11 (quin, J=6.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([C:20]1[CH:21]=[C:16]([Cl:15])[CH:17]=[C:18]([CH3:23])[C:19]=1[OH:22])=[O:5]
Reactant: Cc1cc(Cl)ccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: Cc1cc(Cl)cc(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)c1O
Temperature: 0 °C
Yield: 58.5 %

Procedure:
5.06 g of 2-chloro-4-methylsulfonylbenzoyl chloride are added in portions at room temperature to a mixture of 2.85 g of 4-chloro-2-methylphenol and 5.40 g of aluminum chloride in 100 ml of 1,1,2,2-tetrachloroethane, and the mixture is subsequently refluxed for 7 hours. When cold, the reaction mixture is poured onto 200 g of ice and 500 ml of concentrated hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted twice using 50 ml of dichloromethane. The combined organic phases are washed until neutral, dried over magnesium sulfate and evaporated. Recrystallization from a mixture of ethyl acetate and diisopropyl ether gives 4.2 g (60% of theory) of 2,5'-dichloro-2'-hydroxy-3'-methyl-4-methylsulfonylbenzophenone in the form of colorless crystals with a melting point of 175°-180° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][NH2:23])[N:17]=3)=[N:13][C:12]=2[CH3:24])=[O:10])[CH:2]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.O.[Cl-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][NH:23][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)[N:17]=3)=[N:13][C:12]=2[CH3:24])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn(CCN)n2)sc1C(=O)NCc1cccnc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccn(CCNC(=O)c3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 415.7 %

Procedure:
To a solution of 2-[1-(2-amino-ethyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide (0.1 g, 0.29 mmol) in methylene chloride (5 mL) was added 4-fluoro-benzoyl chloride (0.07 mL, 0.44 mmol) and triethyl amine (0.08 mL, 0.58 mmol). The reaction mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), water (100 mL) and brine (100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 2-{1-[2-(4-fluoro-benzoylamino)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide as a white solid (0.56 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.63 (bs, 1H), 8.57 (d, J=4 Hz, 1H), 7.70-7.81 (m, 3H), 7.46 (d, J=2 Hz, 1H), 7.29-7.33 (m, 1H), 7.09 (t, J=8 Hz, 2H), 6.84 (d, J=2 Hz, 1H), 6.84-6.88 (m, 1H), 6.10-6.15 (bm, 1H), 4.65 (d, J=4 Hz, 2H), 4.42 (bt, J=5 Hz, 2H), 3.89-3.97 (m, 2H), 2.75 (s, 3H); MS (M+H)+=464.8; Rt=1.04 min; HRMS (M+H)+=465.15.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11](Br)=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:37])=[C:32](B(O)O)[CH:33]=1>CCO.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[CH:32][C:31]=3[CH3:37])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1Br
Reactant: Cc1ccc(Cl)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1C
Temperature: 100 °C
Yield: 86.7 %

Procedure:
To a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-bromo-1H-pyrrole-3-carboxylate (prepared according to WO2007/110344, 2.0 g, 6.43 mmol) dissolved in EtOH (20 mL) and toluene (20 mL), LiCl (408 mg, 9.64 mmol), 1 M aq Na2CO3 (17 mmol), 5-chloro-2-methylphenylboronic acid (1.423 g, 8.35 mmol) and Pd(Ph3P)2Cl2 (470 mg, 0.67 mmol) were added and the reaction mixture was heated at 100° C. for 5 h. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure, dissolved in DCM and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM/EtOAc 50/50) to afford the title compound (1.99 g, 87%).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl.[CH3:54][N:55]([CH3:61])[CH2:56][CH2:57][C:58](O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][N:30]([C:58](=[O:59])[CH2:57][CH2:56][N:55]([CH3:61])[CH3:54])[CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CN(C)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt (1.50 g, 2.37 mmol) was diluted with DCM (10 mL) and added to a pre-activated mixture of 3-(dimethylamino)propionic acid HCl salt (383 mg, 2.49 mmol), HATU (1034 mg, 2.72 mmol) and DIEA (831 uL, 4.77 mmol) in DCM (10 mL). The round-bottomed flask was flushed with argon and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated. Purification by silica gel chromatography with a DCM/MeOH gradient yielded (Z)-((3-(dimethylamino)propanoyl)azanediyl)bis(ethane-2,1-diyl) dioleate.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate (10.34 g, 23.17 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (9.51 g, 95.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.18 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1C
Yield: 100.5 %

Procedure:
This compound was prepared in a manner analogous to Step E, Example 1. Here, 8.2 grams (0.0206 mole) of methyl 6-chloro-2-methyl-3-[6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl]benzoate was combined with 5.7 grams (0.410 mole) of potassium carbonate and 4.4 grams (0.309 mole) of methyl iodide in 200 mL of THF. The reaction product was purified by column chromatography on silica gel using mixtures of EtOAc and hexane as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 7.8 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2>[Pd].C(O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccc(C(=O)NC3CN4CCC3CC4)o2)cc1
Reaction time: 2 h

Procedure:
A mixture of 5-(4-nitro-phenyl)-furan-2-carboxylic acid(1-aza-bicyclo[2.2.2]oct-3-yl)-amide (5.0 g, 14.6 mmol), palladium on carbon (0.5 g, 10%) and ethanol (250 ml) was stirred under hydrogen atmosphere for 2 hours. The palladium was filtered off on celite. The crude mixture was purified by silica gel chromatography, using a mixture of dichloromethane:methanol (9:1) and 1% methanol as eluent. Yield 2.5 g (55%). M.p. 103-113° C.
Reaction SMILES: C([O:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:15])=[C:11]([F:14])[CH:12]=2)[N:7]([C:16](=[O:18])[CH3:17])[C:6]=1[CH3:19])(=O)C.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[C:16]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=2)[C:5](=[O:4])[CH:6]1[CH3:19])(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1c(C)n(C(C)=O)c2cc(Br)c(F)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2cc(Br)c(F)cc2C(=O)C1C
Temperature: 110 °C
Yield: 72.3 %

Procedure:
To a mixture of 1-acetyl-6-bromo-5-fluoro-2-methyl-1H-indol-3-yl acetate (D87) (1.22 g, 3.72 mmol) in ethanol (15 mL) was added a solution of sodium sulfite (0.562 g, 4.46 mmol) in water (15.00 mL). The mixture was then heated at 110° C. for 2 hours. After cooling to RT, ethanol was removed under reduced pressure. The aqueous residue was poured into water (50 mL) and extracted with DCM (20 mL×3). The organic layers were combined, washed with brine (100 mL), filtered through phase separator and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to give title compound (769.5 mg). LCMS (A): m/z (M+H)+ 286/288, C11H9BrFNO2 requires 285/287 (acidic).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[N:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O.CN([CH:31]=[O:32])C>>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([CH:31]=[O:32])[C:9](=[O:18])[N:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1c(-c2ccncc2)cc(=O)n1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(-c2ccncc2)c(C=O)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a 25 ml round-bottom flask with stirbar was added N,N-dimethylformamide (10.0 ml, 130 mmol). The flask was cooled in an ice water bath, and phosphorous oxychloride (4.2 ml, 45 mmol) was added. The reaction was warmed to room temperature and stirred under nitrogen. After 50 minutes, this was transferred, first via syringe and then pipette, to a solution of 1-methyl-2-phenyl-5-(pyridin-4-yl)-1,2-dihydropyrazol-3-one (3.31 g, 13 mmol) in DMF (18 ml). The flask was placed in a preheated oil bath (120 C), stirred for 12 minutes, and then cooled to room temperature. The reaction was poured into a aqueous solution of 5 N NaOH (40 ml) and diluted with ice water (˜75 ml). More ice and water were added. The aqueous phase was extracted with chloroform and the organic extracts were dried over sodium sulfate, filtered, and concentrated. DMF present, so the crude material was diluted with chloroform and washed with water. The aqueous extractions were extracted with chloroform, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give the crude product. MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C16H13N3O2: 279. Material taken to next step without further purification.