Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]1(C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1>C(O)C.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>[C:9]1([C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1
Reactant: Nc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: CCO
Product: Nc1cncc(-c2ccccc2)c1
Temperature: 90 °C
Yield: 13 %

Procedure:
A mixture of 5-bromopyridin-3-amine (248 mg, 1.43 mmol), Pd(PPh3)4 (50.4 mg, 0.04 mmol), toluene (3 mL), sodium carbonate (2 M, 3 mL, 6 mmol), and phenylboronic acid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL) was heated for 4 hours in an oil bath at 90° C. and allowed to cool to room temperature for 16 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The aqueous phase was washed once more with ethyl acetate, and the combined organic phases were washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (80% ethyl acetate/hexanes) to afford 5-phenylpyridin-3-amine (31.9 mg, 0.19 mmol, 13% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.17-8.42 (m, 1 H), 8.02-8.20 (m, 1 H), 7.32-7.62 (m, 4 H), 7.25 (s, 1 H), 7.06-7.20 (m, 1 H). MS (LC/MS) R.T.=0.91; [M+H]+=171.09.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@@H:14]2[C:18]([OH:20])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@@H:14]2[C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(CC1C=Cc2ccccc21)C1SCN[C@@H]1C(=O)O
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(CC1C=Cc2ccccc21)C1SCN[C@@H]1C(=O)N1CCCC1
Yield: 44 %

Procedure:
Colorless crystals of 1-[3-(2-indenylacetyl)-L-thioprolyl]pyrrolidine were prepared in the same manner as in Example 1, except that 3-(2-indenylacetyl)-L-thioproline prepared in Reference Example 19 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 44%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[C:20]#[N:21].O>CS(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:18]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=2[C:20]#[N:21])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Oc2ccccc2)cc1
Temperature: 75 °C
Yield: 87.2 %

Procedure:
To a solution of 5.71 g (0.0307 moles) of 4-phenoxyphenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 75° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 4 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried. The crude product was dissolved in CH2CL2 and washed with 10% aqueous NaOH, water and dried (Na2SO4). Removal of solvent in vacuo afforded 8.0 g (87% yield) of product. Recrystallization from ethanol gave purified 2-(4-phenoxyphenoxy)-5-nitrobenzonitrile, mp 150°-151.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:16](OC(OCC)(OCC)C)[CH3:17]>C(O)C>[CH3:16][C:17]1[N:6]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Solvent: CCO
Product: Cc1nc2ccccc2c(=O)n1-c1nnn[nH]1

Procedure:
A mixture of 3.8 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide and 3.3 g of 1,1,1-triethoxyethane in 50 ml of ethanol was heated at reflux for 18 hours. The mixture was then concentrated to a small volume and the resulting solid was collected by filtration and air dried to give 2-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 225°-226° C. This compound has the following structural formula: ##STR5##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCOc1ccc2nc(Sc3ccccc3)n(-c3ccc(C)cc3)c2c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
150 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2 ml of dimethylformamide, mixed with 54 mg of potassium carbonate and 40 μl of thiophenol, and the mixture was stirred for 5 hours at 140° C. After cooling, it was mixed with saturated ammonium chloride solution, diluted with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 158 mg was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([F:31])=[CH:24][C:23]=1F.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.CCCCCC>[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([F:31])=[CH:24][C:23]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(F)c([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 158 %

Procedure:
A 100 mL flask was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00 g, 3.71 mmol obtained from Example 5, step B), 1,2,4-trifluoro-5-nitrobenzene (1.32 g, 7.43 mmol), potassium carbonate (1.03 g, 7.43 mmol), and DMF (25 mL). The solution was allowed to stir overnight at room temperature for 3 days. The crude material was isolated by filtration and flash chromatography (EtOAc/Hexane 1:3) to afford 2.50 g (55%) of the desired product. LRMS M+1 (426.9) observed.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:11]2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[Br-].[Li+].CC(OC)(C)C>C(#N)C>[C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:11]2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)s2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(C)(C)C)s1
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
Dimethyl 2-(5-tert-butylthiophen-2-yl)piperidine-1,4-dicarboxylate (2.49 g, 7.34 mmol) was dissolved in acetonitrile (20 mL). Water (0.400 mL) and lithium bromide (5.10 g, 58.68 mmol) were added. After 5 min, TEA (4.09 mL, 29.34 mmol) was added and the reaction heated at reflux for 1 h. MTBE (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (150 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and extracted with MTBE (2×300 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo yielding 2-(5-tert-butylthiophen-2-yl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.125 g, 47.1%) as a white foam. MS m/z 326 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([NH:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccnc1N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ncccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2,3-diaminopyridine (45 g), ethanol (500 ml), triethylamine (42 g) and benzyl bromide (70.5 g) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue partitioned between chloroform (500 ml) and water (400 ml). The organic layer was eparated, filtered through a silica gel plug and evaporated in vacuo. The residue was triturated with hot chlorobutane to yield a brown powder.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:17][O:18][CH2:19][CH3:20])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.CC(C[AlH]CC(C)C)C>C1COCC1>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C:5]1([CH2:17][O:18][CH2:19][CH3:20])[CH:3]=[O:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CCOCC1(C=O)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 59 %

Procedure:
To a stirred solution of 2-ethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.00 g, 3.48 mmol, prepared using the procedure of preparation 3 step 1) in THF (40 mL) at −78° C. under nitrogen was added DIBALH (4.09 mL of 1.7 M solution in PhCH3, 6.96 mmol) dropwise over 15 minutes such that the internal temperature did not exceed −75° C. After 4.5 hours the reaction mixture was quenched by addition of sodium sulfate decahydrate (4 g) and MeOH (0.5 mL) and then warmed to ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc (200 mL), and the combined filtrates were concentrated in vacuo to a colourless oil. Purification by chromatography (silica, 10-30% EtOAc in hexanes) gave 2-ethoxymethyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.528 g, 2.05 mmol, 59%) as a clear, colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[C:22]([O-])(O)=[O:23].[Na+]>CO.CCOC(C)=O>[CH3:22][O:23][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (2 g, 7.6 mmol) in MeOH (26 mL) was added a solution of NaOMe (1.3 g, 23 mmol) in MeOH (40 mL). The mixture was heated at reflux for 24 hr. Additional NaOMe (1.3 g) was added. Continue heating at reflux for 24 hr, and then add additional NaOMe (1.3 g). Continue heating at reflux for 24 hr and cool to rt. Dilute with EtOAc and was with sat. aq. NaHCO3. The solids were removed by filtration. Separate phases and wash organic extract with additional sat. aq. NaHCO3. Dry organic extracts over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 25% ethyl acetate/hexanes) to afford 1.4 g (71%) of (1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as an oil: 1H NMR (CDCl3) δ 3.04-3.08, 3.23-3.29, 3.91, 4.75-4.78, 5.18, 5.42-5.45, 7.25-7.34, 7.57-7.61; MS (ESI+) for C14H15N3O2 m/z 258 (M+H)+.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].C(N(CC)CC)C.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>C(Cl)(Cl)Cl>[CH2:13]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[SH:1](=[O:3])=[O:2])[CH2:14][CH2:15][CH3:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCNCCCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)[SH](=O)=O

Procedure:
To a stirred solution of 160.6 ml sulfuryl chloride in 1000 ml chloroform in a round bottomed flask equipped with a dropping funnel, thermometer, and magnetic stirrer was added dropwise 139.4 ml triethylamine and 168.5 ml dibutylamine with cooling in an ice-water bath to maintain a temperature of 15°-20° C. After the addition was complete, the reaction mixture was stirred without cooling for an additional hour, then poured into a mixture of ice and water (2000 ml). The chloroform phase was separated and washed with 10% hydrochloric acid (1000 ml) followed by ice cold water. The solution was dried over anhydrous calcium chloride (4-20 mesh). Evaporation of the solvent gave 147.7 g N,N-dibutylsulfonamide as a colorless oil.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C1C=CC=CN=1)C.[CH3:27][C:28]1([CH3:36])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]1O>ClCCCl.C(Cl)Cl>[CH3:27][C:28]1([CH3:36])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]1[O:14][C:13](=[O:15])[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1(C)CCC(C)(C)C1O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)OC1C(C)(C)CCC1(C)C
Reaction time: 96 h

Procedure:
To a stirred solution of 2 g (0.008 mol) of N-Cbz-2-aminoisobutyric acid in dry Cl(CH2)2Cl containing 1.9 g dicyclohexylcarbodiimide and 0.1 g dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 1.3 g of 2,2,5,5-tetramethylcyclopentanol dissolved in CH2Cl2. After stirring for 4 days, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([O-])=[O:6].C[CH2:18][N:19](CC)CC.CN.CCO.Cl>CO.CCOC(C)=O>[CH3:13][O:12][C:10]1[CH:11]=[C:3]2[C:4](=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15])[C:5](=[O:6])[N:19]([CH3:18])[CH2:2]2
Reactant: CCN(CC)CC
Reactant: COc1cc(CBr)c(C(=O)[O-])cc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)C2
Temperature: 70 °C

Procedure:
To crude 2-(bromomethyl)-4-methoxy-5-nitrobenzoate (<4 mmol) in methanol (36 mL) was added Et3N (0.68 mL, 4.8 mmol) and methylamine in EtOH (0.6 mL, ˜8 M in EtOH, 4.8 mmol). The mixture was heated to 70° C. for 5 h. and then EtOAc (30 mL) and 2M HCl(aq) (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane then EtOAc-10% MeOH in DCM) gave impure 5-methoxy-2-methyl-6-nitroisoindolin-1-one (487 mg) as a brown solid. The crude material was used directly in the next reaction without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:23]=[C:11]3[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([I:31])C(=O)C1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:23]([I:31])=[C:11]3[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(F)c3)cc2C1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(F)c3)c(I)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of Intermediate 4F (5.0 g, 15.76 mmol) in dichloromethane (25 mL) was added NIS (5.32 g, 23.63 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated to afford Intermediate 4G (6 g, 86%) as colorless semi-solid which was used in the next step without any purification. MS(ES): m/z=444 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.61-7.66 (m, 1H), 7.56 (ddd, J=10.04, 2.51, 1.51 Hz, 1H), 7.39 (td, J=8.03, 6.02 Hz, 1H), 7.04-7.10 (m, 1H), 4.56 (bs, 2H), 4.22 (t, J=5.52 Hz, 2H), 3.92 (t, J=5.52 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-])=O)[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pt]>[Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[NH2:25])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reaction time: 5 h
Yield: 100.3 %

Procedure:
N-[(1S)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-3-nitroquinolin-4-amine (5.46 g, 14.0 mmol) was dissolved in 50 mL of toluene and the solution was placed in a pressure bottle. Platinum on carbon (5%, 1.0 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 5 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with toluene and the combined filtrates were concentrated under reduced pressure to give N′-[(1S)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]quinoline-3,4-diamine (5.05 g) as a brown foam.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[C:31](Br)[CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[C:41](B1OC(C)(C)C(C)(C)O1)([CH3:43])=[CH2:42]>C1COCC1.C(=O)([O-])O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:30]=[C:31]([C:41]([CH3:43])=[CH2:42])[CH:32]=[N:33][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:28]#[N:29])[CH2:21][CH2:22]1)[CH3:27]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: C=C(C)c1cnc2[nH]c3cnc(C#N)c(OC4CCN(CC)CC4)c3c2c1
Temperature: 140 °C
Yield: 165.8 %

Procedure:
9-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile (147 mg, 0.272 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (11 mg, 0.014 mmol) were dissolved in THF (9 mL) and 1N aqueous sodium carbonate (3 mL) added followed by isopropenylboronic acid pinacol ester (0.076 mL, 0.408 mmol) and placed under an argon atmosphere. The reaction mixture was heated under microwave irradiation at 140° C. for 50 min. The cooled reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted into ethyl acetate (4×20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown solid (163 mg) which was used without further purification in the next step. 1H NMR (CDCl3, 300 MHz): 12.05 (br s, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (s, 1H), 8.64 (d, J=2.2 Hz, 1H), 5.48 (s, 1H), 5.28-5.24 (m, 1H), 5.09-4.97 (m, 1H), 3.02-2.91 (m, 2H), 2.49 (q, J=7.2 Hz, 2H), 2.35-2.20 (m, 7H), 2.19-2.07 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:22]([CH2:26][C:27]#[CH:28])[C:23](=O)[CH3:24])(C)(=O)=O>C(O)C>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]2[N:3]([C:22]([CH2:26][C:27]#[CH:28])=[C:23]([CH3:24])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1CNc1cccnc1N
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Solvent: CCO
Product: C#CCc1c(C)nc2c(NCc3ccccc3C)cccn12
Yield: 30.3 %

Procedure:
A solution of 2-amino-3-(2-methylbenzylamino)pyridine (2 g) and 3-mesyloxy-5-hexyn-2-one (1.78 g) in ethanol (40 ml) was refluxed for 31.5 hours and then evaporated in vacuo. The residue was treated with aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (40 g) with a mixtutre of methylene chloride and ethyl acetate (50:1 to 10:1) as an eluent to give 8-(2-methylbenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.82 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=1)[C:18]([O-:20])=[O:19])=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])=[O:2]
Reactant: COc1cc(C=O)c(OCc2cncc(C(=O)[O-])c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C=O)c(OCc2cncc(C(=O)O)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (96 mg, 0.32 mmol, 1 eq.) in a mixture of MeOH/THF (1/3, 8.0 mL) was added NaOH (3 N, 1.7 mL, 5.1 mmol, 16 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid (86 mg, 93%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 10.34 (s, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.96 (d, J=2.0 Hz, 1H), 8.42 (t, J=2.0 Hz, 1H), 8.34 (s, 1H), 7.02 (s, 1H), 5.44 (s, 2H), 3.86 (s, 3H). LRMS (M+H+) m/z 289.1.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:34][CH3:35])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:34][CH3:35])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(OC(F)(F)F)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-[4-(2-{ethyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoate (0.560 g, 1.13 mmol) in THF (50 mL) was added aqueous 0.10 M LiOH (25 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 10 g/70 mL) with ethyl acetate as the eluent afforded 0.457 g (87%) of a colourless oil.