Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8])(=[O:30])[NH2:31]
Reactant: O=C(NCc1ccccn1)c1cc(O)ccc1OCC(F)(F)F
Reactant: NC(=O)CCCCBr
Product: NC(=O)CCCCOc1ccc(OCC(F)(F)F)c(C(=O)NCc2ccccn2)c1
Yield: 45.7 %

Procedure:
Using the general method of Example I Part A, 6.5 g (0.02 mole) of 5-hydroxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide was reacted with 3.3 g (0.018 mole) of 5-bromovaleramide to give 3.5 g of white powdery 5-(4-carbamoylbutoxy)-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide, m.p.138°-139° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH:8]=[CH:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>O>[S:11]1[CH2:12][CH2:13][CH2:14][S:15][CH:10]1[C@@H:9]1[CH:8]=[CH:7][CH2:6][C@H:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)[C@@H]1CC=C[C@H]1C1SCCCS1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1CC=C[C@H]1C1SCCCS1
Temperature: 80 °C

Procedure:
In a 10 ml. reaction flask equipped with a reflux condenser, there are added 226 mg (0.93 mmol) of trans-methyl-3-(1.3-dithian-2-yl)-4-cyclopentene-2-carboxylate (as prepared in example 6) dissolved in 5 ml. of distilled water and a few mg of sodium hydroxide dissolved in one ml. of distilled water. The mixture is heated to 80° C for 3 hours, then cooled and neutralized by 5% HCl. The solution is extracted with ether and the ethereal layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield trans-3-(1,3-dithian-2-yl)-4-cyclopentene-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:30])[NH:28][CH2:29][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)#[N:4].[CH3:31]I>CN(C)C=O>[C:3]([CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[N:20]([CH3:31])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:30])[NH:28][CH2:29][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)#[N:4]
Reactant: N#CCCn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)NC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)CNC3=O
Reaction time: 1 h

Procedure:
36 mg (1.2 mmole) sodium hydride (80% in mineral oil) are suspended under an atmosphere of nitrogen in 50 mL dry dimethylformamide and 365 mg (1 mmole) 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole added portionwise thereto at ambient temperature. After subsidence of the gas evolution, stirring is continued for 1 hour at 20° C. 0.08 mL (1.25 mmole) methyl iodide is then added thereto and stirring continued for 16 hours at ambient temperature. The solvent is distilled off in a vacuum and the residue is chromatographed on silica gel with toluene/ethanol (95:5 v/v). The fraction with an Rf of 0.3 in dichloromethane/methanol (95:5 v/v) is isolated and recrystallized from tetrahydrofuran. 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of pale yellow crystals which decompose above 270° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH2:9]([O:10][C:11]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)=[CH:14][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccc(OCc3ccccc3)cc2)c1

Procedure:
Compound 102 (0.23 g, 7.9 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (15 mL/2 mL/15 mL) was treated with 4-benzloxy phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction mixture was treated with 2 N HCl aq and extracted with EtOAc. The EtOAc layer was washed with saturated NaHCO3 aq, brine and dried over MgSO4. After filtration, the residue was chromatographed on silica gel (1:4 EtOAc/hexanes) to yield the desired product as an orange solid. The orange solid thus obtained was triturated with CH2Cl2 to yield the pdt (2.4 g) as a white solid: Mp=186-187° C.; 1H NMR (DMSO-d6) δ 9.90 (br s, 1 H), 9.05 (br s, 1 H), 7.65 (d, 1 H, J=8.5 Hz), 7.51-7.31 (m, 5 H), 7.19 (d, 1 H, J=8.5 Hz), 7.17 (d, 2 H, J=8.6 Hz), 7.02 (d, 2 H, J=8.7 Hz), 6.86 (dd, 1 H, J=8.5 Hz, 2.4 Hz), 6.70 (d, 2 H, J=1.8 Hz), 6.63 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.86 (s, 1 H), 5.14 (s, 2 H); MS 407 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:8]=[CH:7][C:6]=1[NH:17][C:29](=[O:30])[CH:28]([N:20]1[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[N:23]=[C:19]1[CH3:18])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To a solution of 5-tert-butyl-1-(4-fluorophenyl)pyrazol-4-amine (0.03 g, 0.13 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.029 g, 0.13 mmol), followed by diisopropylethylamine (0.033 g, 0.26 mmol) and HATU (0.054 g, 0.14 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.0145 g, 0.034 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.45 (q, J=1.2 Hz, 1H), 7.33-7.24 (m, 2H), 7.16-7.07 (m, 2H), 6.89 (s, 1H), 4.90 (d, J=7.3 Hz, 1H), 2.47 (s, 3H), 1.86 (d, J=7.3 Hz, 3H), 1.11-1.03 (m, 9H); MS: (ES) m/z calculated for C21H23F4N5O [M+H]+ 438.2, found 438.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1C(=O)OC
Reaction time: 96 h

Procedure:
1 eq. of dimethyl 4-hydroxyphthalate, 1.1 eq. of potassium carbonate and 1.1 eq. of 4-methoxybenzyl chloride were stirred in DMF at RT. After 4 days, the mixture was worked up according to a standard procedure. Dimethyl 4-(4-methoxybenzyloxy)phthalate was isolated as a colorless oil. MS: 331 ((M+1)+)
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(Cl)CCl.[CH2:27]([O:34][C:35]([NH:37][C:38]1[CH:39]=[C:40]([CH2:44][C:45]([OH:47])=O)[CH:41]=[CH:42][CH:43]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35](=[O:36])[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][C:45]([N:20]([O:21][CH3:22])[CH3:19])=[O:47])[CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 24.7 g (87 mmol) of (3-{[(benzyloxy)carbonyl]amino}phenyl)acetic acid in 200 mL of dichloromethane (from Step B) was added triethylamine (30.2 mL, 173 mmol) which resulted in some exotherming (+5° C.) and the suspension becoming a solution. After 10 min cooling, HOBt (13.2 g, 87 mmol), N,O-dimethylhydroxylamine HCl (8.5 g, 87 mmol) was added to the solution followed by EDC (16.6 g, 87 mmol) and the resulting mixture stirred at room temperature overnight under nitrogen atmosphere. The solution was transferred to a separatory funnel and washed with 1 M HCl which caused an emulsion. Methanol was added to break up the emulsion and the aqueous was partitioned off. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. Recrystallization of the residue from 1000 mL of 70% hexane in ethyl acetate (heated to reflux and then cooled to room temperature overnight) afforded the title compound (21 g, 74%) as a white solid. LC-MS: m/z (ES) 329 (MH)+.
Reaction SMILES: C1[CH:6]2[O:7][CH:3]([CH:4]3[C:11](=O)[O:10]C(=O)[CH:5]32)C=1.[CH2:13]([CH2:15][NH2:16])O.C([OH:19])C>>[OH:10][CH2:11][CH2:4][C:5]1[C:6]([NH:16][C:15](=[O:19])[CH:13]=1)=[O:7].[O:7]1[CH:3]=[CH:4][CH:5]=[CH:6]1
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Reactant: CCO
Reactant: NCCO
Product: O=C1C=C(CCO)C(=O)N1
Product: c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride (Sigma-Aldrich, St. Louis Mo.; 30.0 g, 0.181 moles) in anhydrous ethyl alcohol (40 mL), a solution of ethanolamine (12.6 g, 0.206 moles) in anhydrous ethyl alcohol (10 mL) was added over a time period of 2 hours to form a mixture. The mixture was then refluxed for about 3.5 hours and was cooled to room temperature and left to stand overnight. The precipitated product that formed during overnight standing was filtered off and washed with 20 mL of anhydrous ethyl alcohol. The collected solid was then dried under reduced pressure giving 18.3 g of white crystals. NMR (d6-DMSO): 2.92 ppm (s, —CH, 2H), 3.41 ppm (m, —CH2CH2—, 4H), 4.77 ppm (bm, —OH, 1H), 5.12 ppm (s, —CH, 2H), 6.55 ppm (s, —CH═CH—, 2H). Purity: ˜100%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]Cl)[CH:3]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:3]=1)[O:10][C@@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13][N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(CC[C@@H](Oc2cc(Cl)ccc2C#N)c2ccccc2)CC1
Yield: 78.3 %

Procedure:
4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile (0.3 g) and 1,1-dimethylethyl piperazinecarboxylate (0.4 g) were subjected to the procedure described for Example 11 to give the product as a clear gum (0.35 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:27]([CH3:29])[CH3:28])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[O:25][CH3:26])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([O:25][CH3:26])[CH:11]=1)[N:8]=[C:7]([CH:27]([CH3:28])[CH3:29])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(OC)cc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cl)cc2c(Cc3ccccc3Cl)c(C(=O)O)c(C(C)C)nc12

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-isopropyl-8-methoxy-quinoline-3-carboxylic acid ethyl ester (20 mg, 0.05 mmol) and 1N NaOH in ethanol. Off white solid (5 mg, 27%). LC-MS (ESI): 404 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.C([Li])CCC.[Cl:34]N1C(=O)CCC1=O.[Cl-].N>C1COCC1>[Cl:34][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Br)c(C)nn12
Reactant: O=C1CCC(=O)N1Cl
Agent: N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: -78 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Under a nitrogen atmosphere dissolve 3-(4-bromo-2-morpholin-4-yl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (116 mg, 0.25 mmol) in THF (1.5 mL) and chill to −78° C. Add n-butyl lithium (0.1 mL. 2.5 M in hexane, 0.25 mmol) and stir at −78° C. for 30 min. Add N-chlorosuccinimide (33.4 mg, 0.25 mmol) and stir for another 30 min, slowly warming to room temperature. After stirring overnight, quench the reaction by adding a solution of saturated ammonia chloride and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes:dichloromethane:ethyl acetate (5:5:2) to provide the title compound (54 mg). MS (APCI) m/z (35Cl) 420.6 (M+1)+; 1H NMR (400 MHz, CDCl3): 6.44 (s, 1H), 3.79 (t, 4H, J=4.8 Hz), 3.63-3.56 (m, 1H), 3.47 (t, 4H, J=4.8 Hz), 2.55 (s, 3H), 2.45 (s, 3H), 1.88-1.75 (m, 4H), 0.87 (t, 6H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.C[N:25](C)C=O.C1COCC1.Cl>CO>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[CH2:8][NH2:25])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(Oc1ccc(F)cc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CN)Oc1ccc(F)cc1
Temperature: 65 °C

Procedure:
Into a 1 L-single neck round-bottom flask was added 2-(4-fluorophenoxy)-2-methylpropanoic acid (5.10 g, 0.0257 mol), methylene chloride (66.0 mL, 1.03 mol), oxalyl chloride (3.27 mL, 0.0386 mol) and N,N-dimethylformamide (20 μL, 0.0003 mol). The reaction was stirred until bubbling had stopped. Volatiles were removed and crude product then dissolved in DCM and 15 mL of 7N ammonia in MeOH was added. Volatiles were removed and crude product then dissolved in DCM and 15 mL of 7N ammonia in MeOH was added. Borane-dimethyl sulfide complex (5.7 mL, 0.064 mol) was added to the amide in THF (50 mL, 0.6 mol) at room temperature. The reaction was heated at 65° C. overnight. MeOH was added carefully. 1 N HCl was added and was heated at 65° C. for 2 hours. The reaction was concentrated in vacuo. The solid was dissolved in water and was washed with DCM. The aq. layer was basified with 1 N NaOH. The reaction was extracted with DCM. The reaction was dried with MgSO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:26]1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: F[C@@H]1CCNC1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(N3CC[C@@H](F)C3)n2n1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol) and (R)-3-fluoropyrrolidine (109 mg, 1.22 mmol) in NMP (1.85 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (60 mg, 26%). 1H NMR (DMSO-d6) δ: 10.77 (s, 1H), 7.24-7.35 (m, 2H), 7.11-7.25 (m, 3H), 6.93 (s, 2H), 5.95 (s, 1H), 5.30-5.61 (m, 1H), 3.74-4.41 (m, 4H), 2.01-2.47 (m, 6H), 1.48 (dt, J=9.0, 4.7 Hz, 1H), 1.29-1.42 (m, 1H). ESI-MS: m/z 380.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH:21]([CH3:24])[CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH:21]([CH3:24])[CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: CC(CCl)CBr
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCl)CC(C#N)(C#N)Cc1ccc(C(F)(F)F)cc1
Yield: 61.5 %

Procedure:
Using 0.22 g of 2-(4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.33 g of 1-bromo-3-chloro-2-methylpropane, and according to the process described in the Production Example 1, there was obtained 0.19 g of 2-(3-chloro-2-methylpropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (86)).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C[O-].[Na+].[Cl-].[NH4+:17]>CO>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]([NH2:17])=[NH:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of 2-chloro-5-nitro-benzonitrile (913 mg, 5.00 mmol) in MeOH (10 ml) is added powdered sodium methoxide (135 mg, 2.50 mmol) at room temperature. The solution is stirred at 65° C. for one day. Then ammonium chloride (294 mg, 5.5 mmol) is added and the mixture is refluxed for another day. The mixture is cooled to room temperature and the solvent removed in vacuo to give the crude 2-chloro-5-nitro-benzamidine hydrochloride, which is dissolved in THF (20 ml) and water (2 ml). This solution is transferred to a quartz reaction vessel (20 ml) and 2-bromoacetophenone (800 mg, 4 mmol) and potassium hydrogencarbonate (1.5 g, 15 mmol) are added. The reaction vessel is then placed into the cavity of a microwave reactor (Emrys optimizer) and irradiated for 15 minutes at 120° C. After the mixture is cooled to room temperature, the solvent is evaporated and the residue is dissolved in EtOAc (50 ml). The organic solution is washed with water (30 ml) and brine (30 ml), dried over MgSO4 and concentrated to give a crude dark oil, which is chromatographed (EtOAc/DCM=1/50) to give 2-(2-chloro-5-nitro-phenyl)-5-phenyl-1H-imidazole as a red solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]([C:18]([OH:20])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:4].O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30]>>[F:1][C:2]([F:21])([F:22])[C:3]([NH:5][C@H:6]([C:18]([O:20][CH:26]1[CH2:27][C:28](=[O:29])[NH:24][C:25]1=[O:30])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])=[O:4]
Reactant: O=C(O)[C@H](CCCCNC(=O)C(F)(F)F)NC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1O
Product: O=C1CC(OC(=O)[C@H](CCCCNC(=O)C(F)(F)F)NC(=O)C(F)(F)F)C(=O)N1

Procedure:
N,N'-bis-trifluoroacetyl-L-lysine is treated with N-hydroxysuccinimide according to Example 2A to obtain N,N'-bis-trifluoroacetyl-L-lysyloxy succinimide; [α]D26 -31.4° (EtOH); νmax (KBr) 1810, 1790, 1740, 1700 cm-1. This product (473 mg) is added under nitrogen to amphotericin B (500 mg) in 5 ml of a 9:1 dimethylsulfoxide:methanol mixture. After 3.5 hours, 6 ml of methanol is added and the mixture is added dropwise to excess ether. A fine, yellow precipitate is allowed to settle with cooling overnight. Filtration, washing with ether and drying gives the named compound: [α]D26 +263.2 (dimethylsulfoxide); νmax (KBr) 1710 cm-1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[C:2]([F:43])[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cn[nH]c3)sc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(F)c(-c3cn[nH]c3)sc2n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 4.8 %

Procedure:
A stirred solution of N-[3-bromo-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridin-4-yl]-3-chlorobenzenesulfonamide (Example 100) (120 mg, 0.248 mmol) in THF (1.5 mL) was cooled to −78° C. using a dry ice/acetone bath. n-BuLi (2.5M in Hexane) (0.109 mL, 0.273 mmol) was added dropwise and the mixture stirred at −78° C. for ca. 1.5 h. Then, N-fluorobenzenesulfonimide (82 mg, 0.260 mmol), pre-dissolved in THF (0.5 mL), was added dropwise and the mixture stirred at −78° C. for ca. 1 h and then left to stir at RT for 3 days (ca. 89 h). The reaction mixture was then quenched with saturated NH4Cl solution (ca. 20 mL), extracted with ethyl acetate (20 mL×3) and the combined organics dried and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in DCM and further purified by MDAP (acidic conditions), to give the title compound (5 mg). LCMS (A) m/z: 423 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[H-].[Na+].[Cl:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>CN(C=O)C>[ClH:16].[ClH:16].[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[N:6]2[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc(C)c2c1NC(=O)C2=O
Reactant: ClCCN1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c2c1C(=O)C(=O)N2CCN1CCN(Cc2ccccc2)CC1
Product: Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4,7-Dimethyl-1H-indole-2,3-dione (700 mg) in dry DMF (10 ml) was cooled to 0° C. and sodium hydride (80% dispersion in mineral oil, 120 mg) was added. After 30 minutes at 0° C. 1-(2-chloroethyl)-4-(phenylmethyl)piperazine (1 g) in dry DMF (5 ml) was added. The mixture was heated to 80° C. for 2 hours and then evaporated under reduced pressure. The residue was subjected to flash chromatography and then treated with ethanolic HCl to give 4,7-dimethyl-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dione dihydrochloride, m.p. 223°-227° C. (dec.).