Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:22](=[O:23])[C:21]2[C@@H:20]3[C:24]([CH3:26])([CH3:25])[C@@:17]([CH3:27])([CH2:18][CH2:19]3)[C:16]=2[NH:15]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH:5]1([CH2:4][N:15]2[C:16]3[C@@:17]4([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:20]([CH2:19][CH2:18]4)[C:21]=3[C:22](=[O:23])[N:14]2[C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CC1CC1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
A mixture of (bromomethyl)cyclopropane (2 mL, 20.6 mmol), (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 414 mg, 1.36 mmol) and tetra-n-butylammonium iodide (0.80 g, 2.2 mmol) in N,N-dimethylformamide (5 mL) was heated in a sealed tube in an oil-bath at 100° C. for 20 h. The reaction mixture was cooled to room temperature and then diluted with dichloromethane (200 mL). The solution was washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL), then dried (magnesium sulfate), filtered, and evaporated, and the residue was purified on an Isco 120 g column, eluting with 30-100% ethyl acetate/hexanes to give (4S,7R)-1-(cyclopropyl)methyl-7,8,8-trimethyl-2-(2,4-difluoro-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (209 mg, 43%) as an pale yellow gum. APCI-MS (M+H) 359.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CNC(=O)C=2C=1.[Cl:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][CH2:30][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: ClCCCI
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cnc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCCCl)c(=O)c2cc1OC

Procedure:
3-(3-chloropropyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4-(3H) quinazolinone (1.61 g, 8 mmol). The quinazolinone was combined with 1-chloro-3-iodopropane (1.9 mL, 8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture diluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 0.70 g (31%); brown solid; m.p. 143° C., MS: 282.8 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([C:18]([N:20]2[CH2:25][C:22]3([O:24][CH2:23]3)[CH2:21]2)=[O:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[F:12].[N+:26]([NH:29][C:30]([NH2:32])=[NH:31])([O-:28])=[O:27].[OH-].[Na+].[ClH:35].O1CCOCC1>O1CCCC1.CO>[ClH:35].[F:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=2[F:12])=[C:13]([C:18]([N:20]2[CH2:21][C:22]([CH2:23][NH:32][C:30]([NH:29][N+:26]([O-:28])=[O:27])=[NH:31])([OH:24])[CH2:25]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(CO2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N=C(NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1)N[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a mixture of 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-(1-oxa-5-azaspiro[2,3]hex-5-ylcarbonyl)aniline (0.15 g, 0.33 mmol), prepared using procedures similar to those described in Example 21, and nitroguanidine (0.1 g, 1.00 mmol) in tetrahydrofuran (3.00 mL) an aqueous solution of sodium hydroxide (1.0 mL, 2.0 mmol) was added and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (80 μL, 0.33 mmol) was added to the solution. A white precipitate formed and was collected by filtration. The solid was washed with hexane, and dried to afford 76 mg (38%) 1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidine hydrochloride. 1H NMR (400 MHz, d4-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H), 7.29 (m, 1H), 7.02 (m, 1H), 6.63 (m, 1H), 4.22 (m, 1H), 4.01 (m, 2H), 3.86 (m, 1H), 3.51 (d, 2H); MS (EI) for C18H16F3IN6O4: 565 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.I.[NH2:16][C:17]1[C:18]([C:25]([NH:27][C:28](=[NH:31])SC)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1>O1CCCC1>[NH2:16][C:17]1[C:18]([C:25]([N:27]=[CH:28][NH:31][N:2]2[CH2:7][CH2:6][S:5][CH2:4][CH2:3]2)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: C1CSCCN1
Agent: Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(N)c(C(=O)N=CNN2CCSCC2)nc1Cl
Temperature: 0 °C

Procedure:
Thiomorpholine hydrochloride (2.10 g., 0.015 mole), triethylamine (2.1 ml., 0.015 mole), and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide (1.94 g., 0.005 mole) are heated in tetrahydrofuran (50 ml.) at reflux for 4 hrs. The reaction mixture is added to ice-water to precipitate 590 mg. of 3,5-diamino-6-chloro-N-[(4-thiomorpholinyl)aminomethylene]-2-pyrazinecarboxamide which melts at 234°-6° C. after reprecipitation from dilute hydrochloric acid with sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][N:20]=2)[C:13]([O:15]CC)=[O:14])=[CH:4][C:3]=1[O:21][CH3:22].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][N:20]=2)[C:13]([OH:15])=[O:14])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)c1ccnc(-c2cc(OC)c(Cl)c(OC)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1Cl

Procedure:
To a solution of ethyl 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinate (8.55 g) in ethanol (80 mL) was added 2 M sodium hydroxide (100 mL). The mixture was refluxed for 30 min and evaporated. The aqueous layer was neutralized by 1 M hydrochloric acid and precipitates were dissolved in a mixed solvent of ethyl acetate-THF (3:1). After drying over anhydrous sodium sulfate, the solvent was evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CCCCC.[CH2:28](Br)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:28]([N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CCc2ccccc2)C(=O)C3)c1
Temperature: 0 °C

Procedure:
A solution of 10.0 g (37 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 250 ml of anhydrous dimethylformamide was added with stirring to a suspension of 2.8 g (55.5 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 125 ml of anhydrous dimethylformamide heated at 50° under nitrogen. The mixture was heated at 90° for 2 hours, then cooled to 40°, at which time a solution of 14.0 g (74 mmoles) of phenethyl bromide in 20 ml of anhydrous dimethylformamide was added and the reaction mixture heated at 90° overnight. The cooled solution was poured into ice-water and extracted with ether. Evaporation of the ether gave an oil which was purified by column chromatography (Silicar CC-7, eluting with acetone-benzene). The major fraction was identified as N-phenethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>CN(C)C(=O)C.[Zn].O>[C:31]([Si:28]([O:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:36][CH:35]=1)([CH3:30])[CH3:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: IC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.2 %

Procedure:
To a mixture of zinc powder (5.52 g, 84.5 mmol) and Celite (1.1 g) in N,N-dimethylacetamide (14 ml) was added dropwise chlorotrimethylsilane (0.930 ml, 7.33 mmol) in 1,2-dibromoethane (0.665 ml, 7.54 mmol) at 0° C. under nitrogen atmosphere. The mixture was warmed to room temperature, and stirred for 20 minutes. 8-Iodo-1,4-dioxa-spiro[4.5]decane (18.1 g, 67.6 mmol) in N,N-dimethylacetamide (34 ml) was then added dropwise at 0° C. The mixture was stirred for 30 minutes at room temperature, and the supernatant solution was added dropwise to the mixture of (4-bromobenzyloxy) (tert-butyl)dimethylsilane (15.7 g, 52.0 mmol), copper iodide(I) (792 mg, 4.16 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II)dichloromethane complex (1.70 g, 2.08 mmol) in N,N-dimethylacetamide (74 ml) at room temperature under nitrogen atmosphere. The mixture was stirred at 80° C. for 5 hours. The mixture was poured into the cold water, and extracted with ethyl acetate. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=92/8) to afford tert-butyl-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)benzyloxy]dimethylsilane as a pale yellow oil (14.0 g, 38.6 mmol, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([S:12][CH2:13][C:14](OCC)=[O:15])=[C:7]([NH2:19])[N:6]=1)=[O:4]>C(O)(=O)C>[F:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]2[NH:19][C:14](=[O:15])[CH2:13][S:12][C:8]=2[CH:9]=1
Reactant: CCOC(=O)CSc1cc(F)c(C(=O)OC)nc1N
Solvent: CC(=O)O
Product: COC(=O)c1nc2c(cc1F)SCC(=O)N2
Yield: 105 %

Procedure:
A solution of the fluoropyridine (b) (1.7 g) in acetic acid (100 ml) was heated at 110° C. overnight, evaporated and dried under vacuum to give the product as a white solid (1.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[CH:4]=[CH:3]1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1I.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[NH:11][C:10]1[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=2[N:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(I)c(F)c1
Reactant: Cn1ccc2c(N)ccnc21
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 25 °C

Procedure:
A solution of 260 mg (1.77 mmol) of 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine, 566 mg (2.12 mmol) of 2-fluoro-1-iodo-4-nitrobenzene, 81 mg (0.09 mmol) of tris(dibenzylidene-acetone)dipalladium, 98 mg (0.18 mmol) of 1,1′-bis(diphenylphosphino)ferrocene and 238 mg (2.47 mmol) of sodium tert-butoxide in 8 ml of degassed toluene is stirred at 100° C. overnight. After cooling to RT, the reaction mixture is applied directly to a silica gel column and separated (mobile phase: cyclohexane/ethyl acetate 10:1 to 1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][C:24]([NH:26][CH:27]([CH:34]([CH3:36])[CH3:35])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:10](=[O:22])[C:11]([N:14](C(=O)C(F)(F)F)[CH3:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][C:24]([NH:26][CH:27]([CH:34]([CH3:36])[CH3:35])[C:28](=[O:33])[C:29]([F:30])([F:32])[F:31])=[O:25])[C:10](=[O:22])[C:11]([NH:14][CH3:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N(C)C(=O)C(F)(F)F)c1=O)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1cnc(-c2ccc(F)cc2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Reaction time: 8 h

Procedure:
To a solution of 2-[2-(4-fluorophenyl)-5-(N-trifluoroacetyl-N-methylamino)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3,-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.58 g) in tetrahydrofuran (5 mL) was added water (10 mL) followed by potassium carbonate (0.76 g). The mixture was stirred overnight, extracted into dichloromethane, washed (water, brine), dried (MgSO4) and evaporated. The residue was purified by chromatography, with dichloromethane:methanol (gradient, 99.5:0.5, 98.5:1.5) as the eluent, to give the title compound; TLC: Rf =0.34, dichloromethane:methanol (98:2); NMR: 0.70-1.0 (m,6), 2.03-2.33 (m,1), 2.71 (d,3), 4.00-4.70 (m,3), 5.63-5.73 (m,1), 7.03 (s,1), 7.17-7.30 (m,2), 7.43-7.60 (m,2), 8.81 (d,1); MS: m/z=429(M+1).
Reaction SMILES: [Si]([N:8]1[CH2:11][C:10]([S:23][CH3:24])([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.C(OCC)(=O)C>O1CCCC1.O>[CH3:24][S:23][C:10]1([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][NH:8][C:9]1=[O:25]
Reactant: CSC1(NC(=O)COc2ccccc2)CN([Si](C)(C)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CSC1(NC(=O)COc2ccccc2)CNC1=O
Yield: 101.4 %

Procedure:
A solution of (24) (516 mg) in dry tetrahydrofuran (THF) (10 ml) was cooled to -10° C. and treated with tetrabutylammonium fluoride (476 mg) and glacial acetic acid (180 mg) in a minimum volume of dry THF. After approximately 15 mins the mixture was poured into a mixture of ethyl acetate and water. The organic phase was separated and washed successively with dilute sodium bicarbonate, dilute hydrochloric acid, and brine, then dried and evaporated. Chromatography on silica gel gave the product (25) (366 mg), a white solid. νmax 3410, 1775 and 1690 cm-1 ; δppm (CDCl3) (90 MHz) 2.24 (s, 3 H), 3.48 and 3.90 (ABq, 2H, J7.0 Hz), 4.50 (s, 2H), 6.24 (s, 1H, exch.), 6.80 to 7.45 (m, 6H, becomes m, 5H, on exch.)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][O:3]1.C(N(CC)CC)C.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=C1.C([Si](C(C)C)(C(C)C)Cl)(C)C>CN(C=O)C>[O:18]([CH2:1][C@@H:2]([OH:3])[CH3:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: C[C@H]1CO1
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](O)COc1ccccc1
Temperature: 150 °C
Yield: 108.6 %

Procedure:
A microwave vessel was charged with (S)-2-methyl-oxirane (0.46 ml, 7.78 mmol), triethylamine (0.33 ml, 2.36 mmol), phenol (222 mg, 2.36 mmol) and DMF (2.0 ml). The mixture was heated by microwave for 20 minutes at 150° C. The reaction was concentrated and dried under reduced pressure. The crude mixture (approximately 9:1) was dissolved in DMF (3.0 ml) and treated with imidazole (160 mg, 2.36 mmol) and Triisopropylchlorosilane (181 mg, 0.94 mmol) overnight at room temperature under nitrogen. The reaction was concentrated under reduced pressure and the crude product was purified via flash chromatography using 3:2/heptane:Ethyl acetate as eluant. Fractions containing product were combined and concentrated to afford (S)-1-Phenoxy-propan-2-ol (390 mg, 62%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH:16]([CH3:18])[CH3:17])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 93.8 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and isopropylamine (0.35 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-isopropyl-2-(trifluoromethyl)benzenesulfonamide (0.50 g, 95%) was provided after purification. MS (ESI) m/z 346. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH:11]([NH:13]CC1C=CC=CC=1)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][CH:5]([CH:11]([NH2:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(C)NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)C(C)N
Yield: 100 %

Procedure:
Five grams of ethyl 2-acetamido-3-benzylaminobutyrate were dispersed in 20 ml of ethanol together with 0.5 of 5% palladium-on-carbon and shaken under 40 psi of hydrogen until hydrogen uptake had ceased. The mixture was filtered through Celite and evaporated to give a 100% yield of ethyl 2-acetamido-3-aminobutyrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[N:14]([O-])=[O:15].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C:9](=[N:14][OH:15])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NO)C(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a 0° C. solution of 1-(3-chlorophenyl)butane-1,3-dione (0.75 g, 3.8 mmol) in 15 mL acetic acid was slowly added sodium nitrite (0.560 g, 8.11 mmol) as a solution in 1.5 mL water. The reaction was stirred at 0° C. for 30 minutes and then warmed to room temperature. After an additional 4 hours, the reaction was poured into aqueous saturated sodium bicarbonate and extracted three times with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated to yield 765.7 mg (89%) of 1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione, which was carried forward without further purification. LCMS (ESI) m+H=226; 1H NMR (400 MHz, DMSO-d6) δ: 7.81 (d, 1H), 7.80 (s, 1H), 7.75 (d, 1H), 7.62 (t, 1H), 2.60 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:24])[NH:16][C:17]2[C:21]([C:22]=1Cl)=[CH:20][S:19][CH:18]=2)=[O:13])[CH3:10].[N:25]1([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:24])[NH:16][C:17]2[C:21]([C:22]=1[N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[O:32])[CH2:26][CH2:27]1)=[CH:20][S:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cscc2[nH]c1=O
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Temperature: 110 °C
Yield: 89.9 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (2.07 g, 10.16 mmol) was added to a solution of 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (39) (2.4 g, 9.24 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (1.99 g, 10.16 mmol) in dry DMA. The solution was heated at 110° C. for 3 h. The solution was cooled and the solvent was distilled. The residue was suspended in water, sonicated briefly, and filtered. The solids were washed by excess water and dried to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (3.47 g, 90%) as white solids. MP 282° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 3.27 (m, 4H), 3.77 (m, 4H), 4.24 (q, J=7.2 Hz, 2H), 6.86 (d, J=3.6 Hz, 1H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.46 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.02 (d, J=3.2 Hz, 1H), 11.30 (s, 1H) ppm; MS m/z=418 amu (M++1).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]1[CH2:34][C:23]2=[C:24]3[N:29]([N:30]=[C:22]2[CH2:21]1)[C:28]([CH3:31])=[C:27]([Cl:32])[C:26]([CH3:33])=[N:25]3)=[O:19])C)(C)(C)C.O1CCOCC1.Cl>C(Cl)Cl>[Cl:32][C:27]1[C:26]([CH3:33])=[N:25][C:24]2[N:29]([N:30]=[C:22]3[CH2:21][N:20]([C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:19])[CH2:34][C:23]3=2)[C:28]=1[CH3:31]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Yield: 97.4 %

Procedure:
A solution of {2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (1.54 mg; 3.08 mmol; 1 eq.) in a 4M solution of HCl 1,4-dioxane (7.7 mL; 30.8 mmol; 10 eq.) and DCM (25 mL) was stirred at room temperature for 2 hours then concentrated in vacuo. After dilution with DCM, the solution was washed with sat. aq. Na2CO3, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (1.2 g, 89%) as a yellow powder. 1H NMR (DMSO-d6) δ 10.12 (br s, 2H), 7.46-7.35 (m, 1H), 7.35-7.26 (m, 1H), 7.18-7.10 (m, 1H), 7.04 (t, J=7.4 Hz, 1H), 4.85 (d, J=8.3 Hz, 2H), 4.67-4.28 (m, 3H), 4.22-3.74 (m, 4H), 3.62-3.45 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.34-2.19 (m, 1H), 2.17-1.98 (m, 1H). HPLC (max plot) 94.7%, Rt 2.61 min. UPLC/MS: (MS+) 400.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]([OH:31])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([OH:31])=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(O)CBr
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.