Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:17]([CH2:19][C:20](OCC)=O)#N.C1(C)C=CC(C=O)=CC=1.[N+](C(C)C)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:19]1([CH3:20])[CH3:17])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(C)cc1
Agent: Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(c2ccc(C)cc2)C1(C)C
Yield: 74 %

Procedure:
A mixture of 576 mg (2.68 mmoles) of (E)-ethyl 2-cyano-3-(p-methylphenyl)-2-propenoate (7) [prepared from ethyl cyanoacetate and p-tolualdehyde (p-methylbenzaldehyde) using the procedure described in Example I for an analogous cyanoester], 0.25 ml (2.78 mmoles) of 2-nitropropane, 398 mg (2.88 mmoles) of anhydrous potassium carbonate, and 2.0 ml of absolute ethanol was heated at reflux for 7 hours. The product was isolated as described in the procedure of Example VIII, affording 511 mg (74% yield) of cyclopropanoid cyanoester 15: bp: 155°-183° C. (bath temperature, 0.15 mm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(Br)c(OCc2ccccc2)c1
Yield: 97.8 %

Procedure:
A mixture of 2-bromo-5-chlorophenol (3.93 g, 18.94 mmol), benzyl bromide (3.42 g, 20 mmol) and potassium carbonate (10 g, 72.46 mmol) in acetone (80 ml) was stirred and refluxed for 3 hours then cooled, evaporated and dissolved in ether/water. The organic phase was dried (magnesium sulphate) evaporated and purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:99) to give 5.51 g of white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.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>[Cl:28][C:4]1[CH:3]=[C:2]([C:30]2[O:29][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: OB(O)c1ccco1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (150 mg, 0.31 mmol) and 2-furanylboronic acid (69 mg, 0.62 mmol) in DME (3 ml) was added potassium tert-butoxide (312 mg, 2.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then purified using an SCX cartridge followed by mass directed autoprep HPLC to afford the title compound (E308). MS (ES+) m/e 476/478 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3CCCCC3)C3C=C(F)C(F)=CC=3N=2)=C(OCC2C=CC=CC=2Cl)C=1.[CH3:72][O:73][C:74](=[O:83])[C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([CH2:81]Br)[CH:76]=1>>[CH3:72][O:73][C:74](=[O:83])[C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([CH2:81][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH3:32])[CH:76]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and (3-bromomethyl-benzoic acid methyl ester CAS Reg. No. 1129-28-8). Brown sticky solid (67%). MS (Turbo Spray): m/z=443.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CNCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzyl amine (0.38 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[2-(naphthalen-2-yloxy)-ethyl]amine solid, m.p. 94° C., (yield 0.61 gm, 90.3%).
Reaction SMILES: [Ca:1].[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5]>>[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[Ca+2:1].[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[Ca+2:1].[Ca+2:1]
Reactant: [Ca]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Ca+2]

Procedure:
In an addition step 220, a suitable source of calcium 224 is added to the citrate solution to form an organic calcium citrate solution 226. Typically this step is performed in a standard well known in the art mixed vessel. This step 220 typically takes up to 30 minutes while mixed. In this step 110, the vessel is typically cooled to a set temperature ranging below 25° C. Cooling jackets known in the art, may be employed on a large scale, or the vessel may be at least partially immersed in a water bath on the small scale, as is known in the art.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:29]([S:32](Cl)(=[O:34])=[O:33])[CH2:30][CH3:31]>C(Cl)Cl>[CH2:29]([S:32]([N:1]([C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:15]3)=[O:11])[C:3]=1[F:28])[S:32]([CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])(=[O:34])=[O:33])[CH2:30][CH3:31]
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone (40 mg, 0.1 mmol, 1.0 eq.) in DCM (10 mL) was added TEA (101 mg, 1 mol, 10 eq.) and propane-1-sulfonyl chloride (0.5 mL, 0.5 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (10 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (41 mg, 62.2%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9](Br)[CH:10]=3)[CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC3N(C4C=CC(C)=CC=4)C4C(OC=3C=2)=CC=CC=4)O1.C([O-])([O-])=O.[K+].[K+].C1COCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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.O.C1(C)C=CC=CC=1>[CH:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[CH2:16][C:14]([C:13]=2[C:12]=34)=[CH:15][CH:2]=1
Reactant: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(N2c3ccccc3Oc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 100 °C

Procedure:
1.14 g (1 eq, 2.0 mmol) of the compound 2, 0.8 g (1 eq, 2.0 mmol) of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-10-p-tolyl-10H-phenoxazine, 0.23 g (0.1 eq, 0.2 mmol) of tetrakis(triphenylphosphine)palladium(0), 1 ml (1 eq, 2.0 mmol) of 2M K2CO3, and 0.65 g (1 eq, 2.0 mmol) of tetrabutylammoniumbromide were put into a 100 ml round bottom flask under an argon gas atmosphere, and THF (50 ml) and toluene (20 ml) were added thereto. The reaction mixture was refluxed at 100° C. for 16 hours. When the reaction solution turned dark brown, water was added, and the resultant solution was extracted with ethylacetate. The extracted organic phase was dried over anhydrous magnesium sulfate and filtered to remove a solvent. The residue was dissolved in a trace amount of toluene and purified on a silica gel column. The resultant solid was recrystallized from toluene and methanol to give a material 1 represented by Formula 10 (0.95 g, 50%). 1H NMR (300 MHz, CDCl3, δ): 8.11(s, 2H), 7.98(s, 2H), 7.81(s, 2H), 7.25-5.87(m, 22H), 2.51(s, 3H), 1.93(m, 4H), 1.21(m, 20H), 0.87(m, 6H), 0.65(broad s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][OH:22].C(N(CC)CC)C>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:21]([CH3:20])[OH:22])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CNO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(O)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of 4-fluorocinnamic acid (2.0 g, 12 mmol), oxalyl chloride (1.65 g, 13 mmol) and N,N-dimethylformamide (four drops) in 40 ml dichloromethane was stirred overnight under nitrogen. The resulting solution was evaporated in vacuo, and the resulting solid redissolved in 10 ml dichloromethane. The resulting solution of 4-fluorocinnamoyl chloride was added dropwise to a cold (5°-10° C.), stirred mixture prepared from N-methylhydroxylamine hydrochloride (1.09 g, 13 mmol) and triethylamine (5 ml, 35 mmol), which had been stirred for 20 minutes. The reaction mixture was allowed to warm to room temperature, then washed successively with aqueous 1N HCl and 1N NaHCO3. The organic solution was then chromatographed on silica gel with 2% isopropanol in dichloromethane. The product was recrystallized from methanol-water, to provide 1.65 g of the titled compound as a white powder, mp 141°-141.5° C.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[O:44]1[C:48]2[C:49]([NH2:53])=[CH:50][CH:51]=[CH:52][C:47]=2[CH2:46][CH2:45]1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:53][C:49]3[C:48]4[O:44][CH2:45][CH2:46][C:47]=4[CH:52]=[CH:51][CH:50]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1cccc2c1OCC2
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cccc4c3OCC4)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 2,3-dihydro-benzofuran-7-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11]OC=S.[CH2:15](Br)C#C.CN(C)CCN>C(O)C.C1COCC1.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]#[CH:15]
Reactant: Cc1ccc(Br)c(SCCOC=S)c1
Reactant: C#CCBr
Agent: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCO
Product: C#CCSc1cc(C)ccc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
To a solution of (2-bromo-5-methylphenylthio)ethoxymethane-1-thione (80.23 g, 275 mmol) in ethanol-THF (2/1) (420 ml), a solution of propargyl bromide (49.13 g, 413 mmol) in ethanol (140 ml) was slowly added dropwise in an ice bath and stirred in an ice bath for 20 minutes. Furthermore, while keeping the mixture in the ice bath, a solution of N,N-dimethylethylenediamine (48.48 g, 550 mmol) in ethanol (275 ml) was added dropwise over 15 minutes. The mixture was kept in the ice bath for 20 minutes, and removed from the ice bath and left at room temperature for 1 hour, followed by further stirring at 30° C. in an oil bath for 2 hours. To a separatory funnel that contained 2N aqueous hydrochloric acid (600 ml) and hexane (500 ml), the reaction mixture was added and extracted as it was. The aqueous phase was extracted with hexane (300 ml), and the organic phase combined was washed with 1N aqueous hydrochloric acid (200 ml). Then, after washing with water (200 ml×2 times), it was dried on magnesium sulfate. The solvent was evaporated to obtain 1-bromo-4-methyl-2-(prop-2-inylthio)benzene (62.35 g, 259 mmol). The yield was 94%.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[OH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].Cl[C:13]1[N:18]=[C:17]2[CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[F:39])[CH2:26][CH2:25]1.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:13]2[N:18]=[C:17]3[CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:24]2[CH2:25][CH2:26][CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[F:39])[CH2:28][CH2:29]2)[CH2:3][CH2:2]1.[C:6]([OH:7])([C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: NC1CC1
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(C)CC4)CC2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CN(C)CC4)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of cyclopropanamine (13.6 mg, 0.237 mmol), 3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine TFA salt (30.9 mg, 0.059 mmol), sodium tert-butoxide (11.4 mg, 0.119 mmol), BINAP (5.5 mg, 8.90 μmol) and Pd2(dba)3 (2.7 mg, 2.97 μmol) in toluene (200 μL) was heated at 90° C. for 14 h. The mixture was directly purified by HPLC Method A to give the title compound as a TFA salt (12.9 mg, 40.2%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 0.53-0.58 (m, 2H), 0.75-0.81 (m, 2H), 1.86-1.96 (m, 2H), 2.02-2.12 (m, 2H), 2.64-2.70 (m, 1H), 2.94-3.02 (m, 1H), 3.08-3.12 (m, 3H), 3.17-3.27 (m, 3H), 3.34-3.42 (m, 2H), 3.59-3.68 (m, 2H), 3.75 (s, 3H), 4.25-4.41 (m, 3H), 6.64-6.69 (m, 1H), 6.70-6.76 (m, 1H), 7.03-7.10 (m, 1H); ESI-MS m/z [M+H]+ 428.4.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@@H:49]3[CH2:53][C:52]([F:55])([F:54])[CH2:51][NH:50]3)=[N:46][CH:45]=2)=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@@H:49]3[CH2:53][C:52]([F:54])([F:55])[CH2:51][N:50]3[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11])=[N:46][CH:45]=2)=[CH:40][CH:39]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: FC1(F)CN[C@H](c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 20 ml, pear-shaped flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (416 mg, 2.38 mmol) and HATU (695 mg, 1.83 mmol) were combined with DMF (10 ml) to give a colorless solution. (S)-5-(4-bromophenyl)-2-(4,4-difluoropyrrolidin-2-yl)-1H-imidazole (600 mg, 1.83 mmol) in 2 ml of DMF was added and followed by drop wise addition of DIPEA (1.18 g, 1.6 ml, 9.14 mmol). It was stirred at room temperature for 1 hr then poured into ice/water. It was extracted with EtOAc (2×30 ml), washed with brine and water. The organic layer was dried over MgSO4, concentrated and purified on a silica gel column (CH2Cl2, 1%, 2%, 5% MeOH/CH2Cl2) to afford methyl (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4,4-difluoropyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl-carbamate as an orange foaming solid. (650 mg, 73%): ESI-LRMS m/e calcd for C20H25BrF2N4O3 [M+] 485. found 486 [M+H+].
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21].[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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]>[C:17]([NH:16][CH2:15][C@@H:13]1[O:12][C:11](=[O:20])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[C:5]([F:21])[CH:6]=2)[CH2:14]1)(=[O:19])[CH3:18]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc(C#Cc2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cc1
Temperature: 70 °C

Procedure:
A mixture of Example 1E (55 mg), 4-methoxycarbonylphenylboronic acid (27.2 mg), and tris(dibenzylideneacetone)dipalladium (15 mg) in degassed dimethoxyethane (1.3 mL) was treated with 2N aqueous Na2CO3 (0.1 mL), heated to 70° C. for 20 hours, and concentrated. The concentrate was dissolved in dichloromethane (2 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:1 hexanes/acetone to provide the desired product. MS (ESI(+)) m/e 411 (M+H)+; MS (ESI(−)) m/e 409 (M−H)−; 1H NMR (300 MHz, CDCl3) δ 8.00 (d, 2H), 7.61 (d, 2H), 7.55 (dd, 1H), 7.50 (t, 1H), 7.20 (dd, 1H), 6.0 (br t, 1H), 4.80 (m, 1H), 4.07 (t, 1H), 3.93 (s, 3H), 3.85-3.75 (dd, 1H), 3.60-3.50 (m, 2H), 2.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][NH:17][CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2ccc3c(c2)C2CNCCC2O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.221 g, 0.53 mmol) was dissolved in CH2Cl2 (7 mL). Trifluoracetic acid (0.81 mL, 20 equiv.) was added, and the reaction mixture was stirred at rt under N2 for 2 h. The reaction mixture was cooled to −5° C. and 2N aqueous NaOH (8 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The water layer was extracted with CH2Cl2 (2×) and with 25:1 CH2Cl2:CH3OH (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Example 245 (0.16 g) was obtained in 98% yield. MS (ESI+) for C17H15Cl2NO m/z 320.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1([OH:18])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].C[O:20][C:21](=[O:44])[C@H:22]([C@@H:41]([CH3:43])O)[NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH2:1]([C:5]1([O:18][C@H:41]([CH3:43])[C@@H:22]([C:21]([OH:44])=[O:20])[NH2:23])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: CCCCC1(O)c2ccccc2-c2ccccc21
Product: CCCCC1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-butyl-9H-fluoren-9-ol (Example 3h) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[C:13]([CH:28]=[C:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:12]4)[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>CO.CN(C)C=O.O>[Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13]([CH:28]=[C:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:12]4)[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C=C3SC(=O)NC3=O)cc3cc(-c4nc5cc(Cl)c(Cl)cc5[nH]4)ccc32)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1NC(=O)C(=Cc2cc3cc(-c4nc5cc(Cl)c(Cl)cc5[nH]4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of 5,6-dichloro-2-[2-[(2,4-dioxothiazolidin-5-ylidene)methyl]-1-(4-methylphenyl)sulfonylindol-5-yl]benzimidazole (100 mg, 0.172 mmol) in methanol (7.5 mL) was added aqueous sodium hydroxide (2 mol/L; 1.5 mL), and the mixture was heated to reflux for 3.5 h. The reaction mixture was cooled on an ice bath, and pH was adjusted to 7. The precipitated products were collected by filtration, washed with water, and dried. To a solution of the product (50 mg) in dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (15 mg, 0.12 mmol), and the mixture was stirred at room temperature for 30 min. Hydrochloric acid (1 mol/L; 0.5 mL) and water were added to the mixture, and the precipitated product was filtered off and washed with water and ethanol to afford 5,6-dichloro-2-[2-[(2,4-dioxothiazolidin-5-ylidene)methyl]indol-5-yl]benzimidazole (18 mg, 24%).