Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2[CH2:7][CH2:8][NH:9][C:10]=2[CH:11]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[N:16]1[CH:21]=[CH:20][C:19]([C:3]2[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]3[CH2:7][CH2:8][NH:9][C:10]=3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(Br)cc2c1CCN2
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2
Reaction time: 12 h
Yield: 100.1 %

Procedure:
To a 100 ml flask was added methyl 6-bromoindoline-4-carboxylate 54.1.B (2000 mg, 7.8 mmole), 4-pyridylboronic acid (1152 mg, 9.4 mmole, available from Maybridge), tetrakis(triphenylphosphine)palladium (1805 mg, 1.6 mmole, available from Strem), 30 ml of DMF and 10 ml of saturated sodiumcarbonate. The reaction was stirred at 70° C. for 18 hours at which time additional tetrakis(triphenylphosphine)palladium (900 mg, 0.8 mmole) was added. After an additional 12 hours, the reaction mixture was partitioned between 1000 ml EtAc and 300 ml of water. The organic solvent was removed by rotary evaporation to give methyl 6-(pyridin-4-yl)indoline-4-carboxylate 54.1.C (1986 mg, 100% yield) which was used with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:6][C:5]2=1.C[C@H](N)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH:15][C@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:6][C:5]2=1
Reactant: C[C@@H](N[C@H]1CCc2[nH]c3ccc(F)cc3c2C1)c1ccccc1
Agent: C[C@H](N)c1ccccc1
Product: C[C@H](N[C@@H]1CCc2[nH]c3ccc(F)cc3c2C1)c1ccccc1

Procedure:
By following the same procedure as (S)-6-fluoro-N—((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine but using (S)-α-methylbenzylamine for the reductive amination, the title compound was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:20])[CH3:19])[CH3:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2ccncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2ccncc2c1
Temperature: 95 °C
Yield: 53.3 %

Procedure:
7-Hydroxyisoquinoline (500 mg, 3.4 mmol), ethyl 2-bromoisobutyrate (3 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) were mixed in 7 ml of anhydrous DMF. The reaction was heated to 95° C. under N2 for 18 hrs. The reaction was concentrated under reduced pressure and purified by flash column chromatography (33% EtOAc/Hexanes) to yield 470 mg (53%) of the title product of this preparation as a yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-(Tetrahydro-3-furanyl)ethanol (230 mg) was dissolved in dry DCM (5 mL) and triethylamine (0.552 mL) was added. The stirred solution was cooled (ice bath) under nitrogen and methanesulphonyl chloride (0.199 mL) was added dropwise over 5 mins. The mixture was allowed to warm slowly to room temperature as the ice bath melted and was left for 16 h. The mixture was shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (364 mg).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:13][C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1>CO>[CH:1]1([NH:4][CH2:13][C:14]2[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: NC1CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(CNC2CC2)c1
Yield: 34.9 %

Procedure:
Cyclopropylamine (5.71 g; 10.0 mmol) and triethylamine (1.01 g; 10.0 mmol) were dissolved in methanol (50 ml). While the mixture was stirred in an ice bath, 3′-bromomethylacetophenone (2.13 g; 10.0 mmol) in methanol (10 ml) was added dropwise. The mixture was removed from the ice bath, and stirred for 18 hours at room temperature. The solvent was evaporated under reduced pressure, and the residue was taken up in 2N hydrochloric acid (100 ml), followed by extraction with diethyl ether (100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→0:1), to thereby yield 0.66 g of the target compound as yellow oily matter (yield: 34.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][CH2:24][Br:23])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCCOCCCBr
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccc(OCCCOCCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.5 %

Procedure:
Under an argon atmosphere, 1 g of [(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester was added to a suspension of 0.16 g of 60% sodium hydride in 15 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 40 minutes and then 4.75 g of bis(3-bromopropyl)ether was added. The mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo to an oil which was dissolved in ethyl acetate, washed with water and concentrated to give an oil which was purified by column chromatography using 7.5% ethyl acetate-toluene to yield 1 g (60%) of [[8-acetyl-7-[3-(3-bromopropoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(Cl)Cl>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)(=[O:16])=[O:17])[CH2:36][C@@H:37]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:38])[CH:1]=[O:3]
Reactant: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cc2)CC1)NO)c1ccccc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C#Cc1ccc(N2CCN(S(=O)(=O)CC(C[C@H](C)c3ccccc3)N(O)C=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To formic acid (3.75 mL, 98 mmol) at 0° C. was added acetic anhydride (750 μL, 7.8 mmol) and the mixture was stirred at 0° C. for 10 minutes. This was added to a solution of 1-{[(4S)-2-(hydroxyamino)-4-phenylpentyl]sulfonyl}-4-[4-(trimethylsilylethynyl)phenyl]piperazine (720 mg, 94 wt %, 1.35 mmol) in CH2Cl2 (5 mL) cooled to 0° C. The reaction was brought quickly to RT and stirred for 20 minutes. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (3×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for two hours. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 40–85% EtOAc in iHexane) and evaporated in vacuo. The solid was dissolved in ether/CH2Cl2 and the insoluble contaminant removed by filtration to give the title compound as a pink foam (90 mg, 0.171 mmol, 15%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C1=O)(=[O:3])C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:1](=[O:3])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)C.C(Cl)(Cl)Cl.ClC1C=CC=[C:30]([C:34]([O:36]O)=[O:35])C=1.S([O-])(O)=O.[Na+]>ClCCl>[C:34]([O:36][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)(=[O:35])[CH3:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)Cc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(-c2ccc(CC(C)OC(C)=O)cc2)cc1
Yield: 96.7 %

Procedure:
29.6 g (0.1 mol) of (-)-4-acetyl-4'-(2-acetoxypropyl)biphenyl (XIX-13) {[α]D20 -9.9° (C=1, CHCl3)} was charged into a four necked-flask provided with a thermometer and an agitator, and dissolved by adding 200 ml of dichloromethane. 20.7 g (0.12 mol) of m-chloroperbenzoic acid was added in this solution and agitated at reflux for 8 hours. After excess of m-chloroperbenzoic acid was decomposed by adding 10% aqueous solution of sodium hydrogen sulfite to the reaction mixture, the organic layer was washed with 10% aqueous solution of sodium bicarbonate and then with water, and dried an anhydrous magnesium sulfate. The resulting dichloromethane solution was concentrated under the reduced pressure to provide 30.2 g (yield: 97%) of (-)-4-acetoxy-4'-(2-acetoxypropyl)biphenyl (XVIII-13).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:34]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35]1>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:39]([C:36]3[CH:37]=[CH:38][O:34][CH:35]=3)(=[O:41])=[O:40])[C:3]=2[F:33])[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (300 mg, 0.612 mmol) in pyridine (3 mL) was added 3-furansulfonyl chloride (153 mg, 0.918 mmol, and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to give 310 mg of the title compound. MS (ESI): 620.2, 622.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[CH:14]=[N:13]1>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([NH:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][N:13]=[CH:14]3)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CC#N
Product: Brc1cn2ccnc2c(Nc2ccc3[nH]ncc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 1.00 equivalent (eq.) of 6,8-dibromo-imidazo[1,2-a]pyrazine and 1.00 eq. of 1H-Indazol-5-ylamine are dissolved in acetonitrile and placed into a sealed tube and heated at 100° C. for 24 hours. The mixture is cooled to room temperature (RT) and partitioned between ethyl acetate (EtOAc) and saturated (sat.) NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (4).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:20](=[O:23])[NH:21][N:22]=2)=[CH:15][CH:16]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(C2=NNC(=O)C(c3ccccn3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2cc(-c3ccccn3)c(=O)[nH]n2)cc1

Procedure:
In a 10 mL round bottom flask, 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-pyridin-2-yl-4,5-dihydro-2H-pyridazin-3-one (120 mg, 0.31 mmol), and cesium carbonate (197 mg, 0.62 mmol), in dimethylsulfoxide (3 mL) was heated to 135° C. 3 h. The reaction was cooled and the slurry was partitioned between methylene chloride and water extracted three times, and then dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5), followed by HCl salt formation produced 120 mg (33%). Mp 157-161° C. MS m/z 391 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[C:5]=1[F:23].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1Cl.OP([O-])(O)=O.[K+]>CS(C)=O>[CH:17]1([O:16][C:9]2[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[C:13]3[C:8]=2[O:7][C:6](=[O:22])[C:5]([F:23])=[C:4]3[NH:3][C:30]2[C:29]([Cl:32])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc2c(N)c(F)c(=O)oc2c1OC1CCCC1
Reactant: Clc1cncc(Cl)c1Cl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(F)c(=O)oc2c1OC1CCCC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (40 mg, 60%, 1.0 mmol) was added to a solution of 4-amino-8-(cyclopentyloxy)-3-fluoro-7-methoxy-2H-chromen-2-one (95 mg, 0.32 mmol), 3,4,5-trichloropyridine (118 mg, 0.65 mmol), and DMSO (3 mL) at rt under N2. After 1.5 h, the reaction was heated at 50° C. for 2 h and then 70° C. for 2 h. The reaction was allowed to cool to rt, poured into 1M KH2PO4 (30 mL) and extracted with ethyl acetate (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (7:3→0:1; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-3-fluoro-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.70 (s, 2H), 7.90 (d, 1H), 7.25 (d, 1H), 4.84 (m, 1H), 3.90 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 438.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[BH3-]C#[N:15].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:15])[CH2:6][CH2:5]2
Reactant: [BH3-]C#N
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(Br)ccc2C1
Reaction time: 20 h
Yield: 276.4 %

Procedure:
This material is commercially available, however, it can be successfully prepared by the following procedure. To a solution of the 6-bromo 2-tetralone (0.288 g, 1.280 mmol) and NH4OAc (0.986 g, 10 eq.) in MeOH (40 mL) is added NaCNBH3 (0.097 g, 1.2 eq) at room temperature. The resulting yellow solution is stirred at that temperature for 20 hours, then acidified with 0.1 M HCl to pH 2.0. The mixture is extracted with CH2Cl2 twice. The aqueous layer is basified with 1.0 N NaOH to pH 10 then extracted with CH2Cl2 three times. The extracts are dried over anhydrous MgSO4 and concentrated in vacuo to afford 0.8 g (44% yield) of the desired product as a yellow oil which is used without further purification. 1H NMR (300 MHz, CD3OD) δ 7.27-7.35 (m, 8H), 7.05 (d, J=8.4 Hz, 4H), 3.56 (m, 1H), 3.17 (dd, J=3.9, 16.2 Hz, 1H), 2.95 (m, 2H), 2.81 (dd, J=9.9, 16.2 Hz, 1H), 2.19-2.29 (m, 1H), 1.79-1.92 (m, 1H); 13C NMR (75 MHz, CD3OD) δ 137.3, 131.5, 131.4, 130.9, 120.1, 47.4, 26.9, 26.7; LRMS: 226.1 (M+H), 209 (M+H−NH3).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]([CH2:10][C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=O)=[O:9].C([O-])(=O)C.[Na+]>O>[Br:2][CH2:3][CH2:4][NH:5][C:11]([CH2:10][C:8]([O:7][CH3:6])=[O:9])=[CH:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: NCCBr
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=C(CC(=O)OC)NCCBr
Reaction time: 0.12 h
Yield: 87.1 %

Procedure:
2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved in water (30 mL) at room temperature (20° C.) with stirring, and dimethyl 1,3-acetonedicarboxylate (10.0 g, 57 mmol) was added. After 5-10 minutes, solid anhydrous sodium acetate (14.35 g, 175 mmol) was added, and stirring continued. After approximately 80 minutes, precipitation of dimethyl 3-(2-bromoethylamino)-2-pentenedioate began, and the solution was stirred for 17 hours at room temperature. The thick slurry was diluted with cold water (20 mL), and aged at 0°-5° C. for 30 minutes and filtered, and the precipitate washed with cold (0°-5° C.) water (50 mL) and dried to constant weight, to afford 13.9 g (86% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as a white solid, m.p. 71°-72° C.,
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[C:5]=1[O:17][CH3:18])[CH:2]=C.I([O-])(=O)(=O)=[O:20].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:18][O:17][C:5]1[C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]([O:11][CH3:12])=[C:9]([CH3:10])[C:4]=1[CH2:1][CH:2]=[O:20]
Reactant: C=CCc1c(C)c(OC)c(OC)c(OC)c1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(CC=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
109 mg of osmium tetroxide were added to a solution of 7.98 of 1-allyl-2,3,4,5-tetramethoxy-6-methylbenzene [prepared as described in step (a) above] in a mixture of 300 ml of dioxane and 100 ml of water, and the resulting mixture was stirred at room temperature for 10 minutes. An aqueous solution of 35.6 g of sodium periodate was then added dropwise, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was freed from the dioxane by evaporation under reduced pressure, and the resulting concentrate was poured into a saturated aqueous solution of sodium chloride, after which it was extracted with diisopropyl ether. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method with mixtures of hexane and ethyl acetate ranging from 8:1 to 5:1 by volume as the eluent, to give 4.64 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:16](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH3:16])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNc1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of 4-bromo-3-methylaniline (3.72 g, 20 mmol) in formic acid (15 mL) was heated at 100° C. for 8 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (50 mL). The layers were separated and the organic layers was dried (Na2SO4) and concentrated. The residue was dissolved in THF (80 mL) and cooled to 0° C. Lithium aluminum hydride (1.52 g, 40 mmol) was added portionwise over 10 min. The mixture was stirred at rt for 8 h and an additional equivalent (750 mg) of LAH was added. After 16 h, the mixture was quenched with EtOAc and MeOH and the solids were filtered. The material was purified by SiO2 flash column chromatography to yield the title compound (2.56 g, 64%) as a colorless oil. 1H-NMR (CDCl3): δ 7.29 (d, 1H, J=8.6 Hz), 6.33 (dd, 1H, J=2.8 Hz), 7.29 (d, 1H, J=2.8, 8.6 Hz), 3.66 (s, 2H), 2.81 (d, 1H, J=5.4 Hz), 2.33 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:24].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[N:13]=[CH:12][C:11]2[C:10]([CH3:26])([CH3:25])[CH2:9][NH:8][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Oc3ccccc3Cl)cc21
Agent: Cl
Product: CC1(C)CNc2cc(Oc3ccccc3Cl)ncc21
Reaction time: 4 h

Procedure:
6-(2-Chloro-phenoxy)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (143 mg) was treated with HCl (saturated solution in ethyl acetate) and stirred for 4 hours. The mixture was then evaporated to dryness in vacuo to give a colourless solid used directly in the next step without further purification. MS: [M+H]+=275.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([F:24])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28].[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[Br:13][C:14]1[C:23]2[C:18](=[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])[C:20]([F:25])=[C:21]([F:24])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: Fc1cc2nccc(Br)c2cc1F
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1c(F)c(F)cc2c(Br)ccnc12
Reaction time: 0.25 h

Procedure:
Diisopropylamine (0.770 mL, 5.41 mmol) was added dropwise to nBuLi (2.3 M in hexanes, 2.14 mL, 4.92 mmol) in THF (25 mL) at −78° C. After stirring for 15 minutes, a solution of 4-bromo-6,7-difluoroquinoline (1.20 g, 4.92 mmol) in THF (25 mL) was added slowly via cannula. After stirring an additional 1.5 hours, chlorotrimethylsilane (0.690 mL, 5.40 mmol) was added dropwise. After stirring one additional hour, the solution was poured into saturated NH4Cl (aq) (100 mL) then diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to afford the title compound as a light yellow solid: 1H NMR (500 MHz, CDCl3): δ 8.60 (d, J=4.7 Hz, 1H); 7.93 (dd, J=10.8, 8.6 Hz, 1H); 7.64 (d, J=4.7 Hz, 1H); 0.49 (s, 9H); LC4: 2.86 min. (M+H) 316.