Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15]([CH2:17]Cl)=O)[CH3:11]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:19])=[C:15]([CH3:17])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Yield: 26.4 %

Procedure:
A stirred mixture of 2,3-diamino-5-methyl-pyridine (4.0 g, 32.5 mmol) and (5.9 g, 36.0 mmol) of ethyl-chloroacetoacetate in 75 ml abs. ethanol was refluxed over night. The ethanol was evaporated under reduced pressure. The residue was dissolved in 2 M HCl and washed 3 times with diethyl ether, pH was adjusted to 9 and extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel with dichloromethane:methanol 95:5 as eluent to give the title product 2.0 g (28%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.CN(C)[C:31](=[O:33])[CH3:32]>C(O)CCO.O.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:32][CH2:31][OH:33])=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: CC(=O)N(C)C
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: OCCCO
Solvent: O
Product: O=C(OCCCO)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
A solution of the compound of Example 51 and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in 1,3-propanediol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred at 120° C. for 2 h then at 100° C. for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and the precipitate was collected by filtration. Ethyl acetate was added to the filtrate, and the precipitate was collected by filtration. Those precipitates were combined then purified by preparative HPLC to afford the titled compound as solid (0.0067 g, y. 16%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.P(Cl)(Cl)Cl.O>C(OCC)(=O)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: O
Product: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
About one-half of the product from Example 17 was dissolved in 25 ml. of dry N,N-dimethylformamide. The mixture was cooled in an ice bath, and 370 mg. (2.7 mmol.) of phosphorous trichloride were added. The mixture was stirred with cooling for 30 minutes. The mixture then was poured into a mixture of water and ethyl acetate. The ethyl acetate solution was separated, washed successively with 5 percent hydrochloric acid and brine, dried over magnesium sulfate, and evaporated to dryness in vacuo. The residue (350 mg.) was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:21][CH3:22])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[CH:15][C:14]=2[CH:20]=1)(=O)=O.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:22][O:21][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[CH:20][C:14]2[CH:15]=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)ccc2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: COc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 55 %

Procedure:
Method A (23 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-2H-1-benzopyran-2-one (see example 67) and 1-phenylpiperazine; yield 55%; fusion point 124° to 125° C. (from ethanol). Fumarate: method E; yield 88%; fusion point 172° to 173° C. (from ethanol).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[NH2-].[Na+].F[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.O>CS(C)=O.C(O)(=O)C>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([O:6][C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCC(O)c1cccs1
Reactant: Fc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Temperature: 87.5 °C

Procedure:
N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (2, racemic hydroxy compound) (50 gm) was dissolved in dimethyl sulfoxide (250 ml). To the clear solution sodamide (13.7 gm) was added at 20-25° C. in small lots within 10-15 minutes under nitrogen atmosphere. The resulting reaction mass was stirred for half an hour to get a clear solution. To this solution 1-fluoronaphthalene (3) (43.4 gm) was added in 20-25 minutes. The temperature was raised to 80-95° C. and stirred for 3-5 hours, then cooled to 25-30° C. Reaction mass added into cold-water (500 ml), pH was adjusted to 5.5-6.0 with acetic acid. Aqueous reaction mass washed with cyclohexane followed by pH adjustment between 10.5-11.0 with caustic solution. Reaction mixture was extracted with cyclohexane and organic layer concentrated under reduced pressure to provide thick oily mass of (±)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (4). The oily mass was dissolved in ethyl acetate (250 ml) and oxalic acid (30 gm) was added. Stirred at 50-60° C. for 1 hour then at 25-30° C. for 2 hours. Solid was filtered and dried to give racemic N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate (5, HA=oxalic acid) as white solid. Yield: 75 gm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:20]1[N:25]=[C:24]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:23]=[C:22]([NH:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[N:21]=1.CCOC(C)=O>C1COCC1>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:20]2[N:25]=[C:24]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])[N:23]=[C:22]([NH:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)[N:21]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 70 °C
Yield: 75.4 %

Procedure:
4-(aminomethyl)phenol (2.4 g) white solid and iPr2NEt (5.0 g) were added into a solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (7.0 g) in THF (150 mL). The mixture was heated at 70° C. for 16 hours. After cooling, the mixture was charged with 250 mL of EtOAc. The resulting solution was washed with water (2×50 mL) and brine (30 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to give a residue which was recrystallized in EtOAc to give 6.54 g of methyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:12][N:11]=[C:10]([CH2:13][CH3:14])[CH2:9]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOCC>O1CCCC1.[Cl-].[Na+].O>[CH2:13]([C:10]1[CH2:9][C@@:8]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:7][OH:6])[O:12][N:11]=1)[CH3:14]
Reactant: CCCCCCCCCCCCCCCCOCC1(CO[Si](C)(C)C(C)(C)C)CC(CC)=NO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCOC[C@@]1(CO)CC(CC)=NO1
Yield: 77.9 %

Procedure:
To a solution of 500 mg of 5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-3-ethyl-5-[(hexadecyloxy)methyl]-4,5-dihydroisoxazole in 10 ml of tetrahydrofuran is added 2.13 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran. After 2 hours the reaction is poured into water, ether and brine. The organic layer is separated, dried and evaporated, to give 300 mg of the desired compound.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C@@H:7]1[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1)=[O:5].[CH:27]1[C:32]([CH:33]=O)=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1>[O:37]1[C:29]2[CH:28]=[CH:27][C:32]([CH2:33][N:10]3[CH2:11][C@@H:7]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[CH2:8][C@H:9]3[C:12]([O:14][CH3:15])=[O:13])=[CH:31][C:30]=2[O:35][CH2:36]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Reaction time: 0.75 h

Procedure:
A solution of methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-tetrahydro-1H-2-pyrrolecarboxylate (19b) (138 mg, 0.38 mmol), piperonal (58 mg, 0.39 mmol) and glacial acetic acid (225 μL, 3.93 mmol) in tetrahydrofuran (2.8 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (125 mg, 1.88 mmol) was added in small portions and stirring was continued for 45 min at the same temperature. After dilution with ethyl acetate (5 mL), the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution (2×5 mL) and brine (5 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 100% dichloromethane and dichloromethane-ethylacetate (4:1, v/v) to give the title pyrrole (20):
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[N:18]2)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[NH4+].[Cl-]>CCO.O.[Fe]>[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[CH:21]=[CH:20][C:19]([NH2:22])=[N:18]2)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc([N+](=O)[O-])n2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc(N)n2)o1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-(3-nitro-pyrazol-1-ylmethyl)-oxazole (219 mg, 0.62 mmol), iron powder (105 mg, 1.86 mmol) and NH4Cl (168 mg, 3.11 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.89 min; [M+H]+=323.42.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH3:9]OS([O-])(=O)=O.C[S+](C)C.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[O:8]1[CH2:9][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: COS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[S+](C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: c1cncc(C2CO2)c1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
To a solution of 2.59 g of 3-pyridinecarboxaldehyde and 62 mg of tetra-n-butylammonium bromide in 60 mL CH2Cl2 at room temperature is added a solution of 10.0 g of trimethylsulfonium methylsulfate in 15 mL H2O. The resulting solution is set stirring and cooled to 0° C. Aqueous NaOH (50% w/w; 40 mL) is added in portions while stirring and the mixture subsequently refluxed for 1 h. After cooling to room temperature, the mixture is filtered and the filtrate extracted with CH2Cl2. The combined extracts are dried over MgSO4, filtered, and concentrated to yield a red oil, which is subjected to Kugelrohr distillation under high vacuum at 150° C. to yield 838 mg of the title compound as a clear, light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.[Li+].[OH-].CC1(C)C2C(=CC=C(C#CC3C=CC(C(O)=O)=CC=3)C=2)NC(OC(C)C)C1>C1COCC1.CCO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:4](=[O:32])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(=O)N3Cc2ccccc2)cc1
Agent: CC(C)OC1CC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(Cc2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Yield: 139.1 %

Procedure:
95.6 mg (0.23 mmol) of ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-benzyl-6-quinolinyl)ethynyl]benzoate (Compound 37) in 2 ml of THF, 2 ml of EtOH, and 1 ml of 1N LiOH were reacted substantially in accordance with the procedure used for the preparation of 4-[4,4-dimethyl-2-isopropoxy-1,2,3,4-tetrahydro-6-quinolinyl]ethynyl benzoic acid (Compound 11) to give the title compound as a white solid (131 mg).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH3:34])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]([Br:1])=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.6 %

Procedure:
Dibromoisocyanuric acid (15.9 g) was added at room temperature to a DMF (150 mL) solution of methyl 3-(benzyloxy)-2′,4′-difluorobiphenyl-4-carboxylate (28.0 g), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (34.0 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[CH3:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[C:30]([F:29])[CH:31]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Cc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1F
Yield: 38 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-fluoro-4-methylphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (38%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10]Br)=[CH:7][CH:6]=1)#[N:4].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC#N>[O:12]1[CH2:10][CH:9]1[C:8]1[CH:13]=[CH:14][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#Cc1ccc(C2CO2)cc1

Procedure:
NaBH4 (1.6 g; 40 mmol) was added to a stirred solution of 4-cyanophenacyl bromide (8.8 g; 40 mmol) in THF (100 mL), and the reaction mixture was stirred until tic indicated that the reaction was complete. The solvent was evaporated and the residue partitioned between DCM and H2O, and the organic layer was separated, dried and concentrated. The residue was treated with K2CO3 (0.08 mol) in MeCN (85 mL) at room temperature overnight. The solvent was removed on a rotary evaporator and the residue partitioned between CH2Cl2 and H2O. The organic layer was washed with H2O (2×100 mL), separated and dried to give the sub-title compound in 90% overall yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:30])[CH3:31])=[O:9]
Reactant: CCN(c1cc(Br)cc(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid (2.0 g, 0.0058 mol) was dissolved in DMSO (20 mL) and 3-(aminomethyl)-4-isopropyl-6-methylpyridin-2(1H)-one (2.1 g, 11.7 mmol) and triethyl amine (0.585 g, 5.8 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PyBOP (4.5 g, 8.7 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, the reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to obtain crude; which then purified by solvent washings to afford the title compound (2.0 g, 68.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 106 %

Procedure:
2-Nitrobenzenesulfonyl chloride (5.79 g) was added to a mixed solution of tetrahydrofuran (20 ml)/water (17 ml) containing (S)-proline (2.00 g), 5 N sodium hydroxide (3.5 ml) and sodium carbonate (3.77 g) under ice cooling, followed by stirring for 1 hour under ice cooling and for 22 hours at room temperature. Water (20 ml) was added to the reaction mixture, and the organic solvent was removed by evaporation under reduced pressure. Then, water (20 ml), 5 N sodium hydroxide (4 ml) and ethyl acetate (100 ml) were added, followed by extraction and solution separation, and the organic layer was extracted again with water (15 ml). Ethyl acetate (50 ml) and 6 N hydrochloric acid (20 ml) were added to the resulting aqueous layer, followed by extraction and solution separation, and the aqueous layer was extracted again with ethyl acetate (50 ml). The resulting organic layer was dried over sodium sulfate, filtered, concentrated and dried under vacuum to obtain (S)-N-(2-nitrobenzenesulfonyl)proline (5.53 g; yield: quantitative).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=2I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Li+].C([O-])(=O)C.[K+].[CH3:25][Si:26]([CH3:31])([CH3:30])[C:27]#[C:28][CH3:29].[Cl-].[NH4+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([N:6]2[C:7]3[C:8](=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[C:28]([CH3:29])=[C:27]2[Si:26]([CH3:31])([CH3:30])[CH3:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC2CCCC2)c(I)c1
Reactant: CC#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(C)c([Si](C)(C)C)n2C1CCCC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of methyl 4-(N-cyclopentylamino)-3-iodobenzoate from above (22.42 g, 65 mmol), palladium acetate (738 mg, 3.28 mmol), lithium chloride (2.757 g, 65 mmol), potassium acetate (12.757 g, 92.30 mmol), and 1-trimethylsilyl-1-propyne (28.70 mL, 192.56 mmol) in 390 mL of DMF was heated at 100° C. for 6 hours. The mixture was added onto 500 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate fraction was dried, evaporated and semi-purified by flash chromatography using silica gel and 0.1% ethyl acetate in hexane. Adding hexane to the semi-purified compound gave 16 g of white crystals (75%).
Reaction SMILES: Cl.[C:2](=[NH:10])([NH2:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:18][C:19]([SH:22])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:18][C:19]1[S:22][N:9]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:10]=1
Reactant: N=C(N)c1ccncc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccncc2)ns1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of isonicotinimidamide hydrochloride (1.0 g, 6.35 mmol) and NEt3 (3.21 g, 4.42 mL, 31.7 mmol) in 50 mL DCM was cooled to −5 and −10° C. Perchloromethyl mercaptan (1.3 g, 763 μl, 6.98 mmol) in 10 mL DCM was added drop wise over 1 h. The mixture was warmed to 0° C. over 30 min and stirred for 2 h. Water (50 mL) and 2M NaOH (10 mL) was added. The suspension was filtrated. The organic layer was extracted with DCM and washed with brine (50 mL) and the aqueous layer was extracted with DCM (50 mL). The organic layers were combined, dried over Na2SO4 and filtered off. The crude product was concentrated under vacuum and the residue dissolved in DCM, taken up on Isolute® and purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield after evaporation of the product containing fraction 0.43 g (34%) of the title compound as a brown solid. MS (m/e): 198.1 (MH+).