Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)[C:14]([CH2:24][O:25][CH2:26][CH3:27])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.B1([C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)OCCCO1>>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:11][C:10]=4[N:9]=[C:8]([NH2:12])[C:7]=3[N:13]=[C:14]2[CH2:24][O:25][CH2:26][CH3:27])[CH2:21][O:20]1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1C[C@H]1COC(C)(C)O1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1C[C@H]1COC(C)(C)O1
Yield: 54.2 %

Procedure:
(S)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.65 g, 6.09 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.19 g, 7.30 mmol) were coupled according to the method described in Examples 118–121. The work-up procedure described in Part F of Examples 125–135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitriled to provide 1.43 g of (S)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 157–158° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>C(OC)(=O)C.[Pt]=S>[NH2:13][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(SC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: S=[Pt]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: COC(C)=O
Product: COC(=O)c1ccc(SC)cc1N

Procedure:
A mixture of methyl 4-(methylthio)-2-nitrobenzoate (11.3 g. 49.7 mmol) and 5% platinum sulfide on carbon catalyst (0.7 g) in methyl acetate (40 mL) was hydrogenated at 750 Psi and 75° C. until hydrogen uptake ceased. The mixture was filtered through Celite®, and the filtrate solvent was rotary evaporated, leaving methyl 2-amino-4-(methylthio)benzoate as a slightly tan crystalline solid (8.7 g) melting at 57°-59° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>>[CH:13]1([CH:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[OH:12])[CH2:15][CH2:14]1
Reactant: Br[Mg]C1CC1
Reactant: O=CC1CCC2(CC1)OCCO2
Product: OC(C1CC1)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (1.135 g, 6.668 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) cooled to −78° C. under argon was added a cyclopropylmagnesium bromide (40 mL, 20 mmol, 0.5 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to afford the product.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][N+:14]([O-])=C(C)[CH:12]=1)[CH3:9]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:12]=[C:11]([O:10][CH2:8][CH3:9])[C:16]([CH3:17])=[CH:15][N:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc(C)[n+]([O-])cc1C
Solvent: ClC(Cl)Cl
Product: CCOc1cc(COC(C)=O)ncc1C

Procedure:
20 ml of acetic anhydride were added dropwise at room temperature to solutio of 7.8 of 4-ethoxy-2.5-dimethylpyridine 1-oxide in 30 ml of chloroform. After boiling under reflux for 3 hours the solution was evaporated, the residue was dissolved in 50 ml of toluene and again evaporated. The residue was taken up in 50 ml of ethyl acetate, whereupon the solution was extracted three times with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 50 g of silica gel with ether and there was obtained (4-ethoxy-5-methyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH2:15])[CH:9]=1>C(O)C.O.C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[N:14]=[C:3]([SH:5])[NH:15][C:10]=2[CH:9]=1
Reactant: S=C=S
Reactant: COc1ccc(N)c(N)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To potassium hydroxide (3.8 g, 0.067M) in ethanol (20 mL) and water (7 mL) was added 2.5 mL CS2 (3.09 g, 0.04M) (H2S trapped over clorox). The reaction mixture was stirred for 30 minutes at ambient temperature, cooled to 0° C., and 4-methoxy-o-phenylene diamine (5.23 g, 0.03M) was slowly added. This reaction mixture was then stirred at reflux for 4 hours, stirred at ambient temperature overnight (basic soln. with pH paper), evaporated in vacuo and diluted with CH2Cl2. Addition of water gave a precipitate which was suspended in CH2Cl2 and acidified to pH 4. Filtration of the suspension gave purple crystalline 5-methoxy-2-mercaptobenzimidazole (3.4 g, 63%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[C:36]2[C:37](=[O:41])[N:38]([CH3:40])[CH2:39][C:35]=2[CH:34]=[CH:33][N+:32]=1[O-:42]>>[CH2:23]([O:22][P:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[C:36]4[C:37](=[O:41])[N:38]([CH3:40])[CH2:39][C:35]=4[CH:34]=[CH:33][N+:32]=3[O-:42])[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=2)=[CH:27][CH:26]=1)(=[O:25])[O:19][CH2:20][CH3:21])[CH3:24]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2cc[n+]([O-])c(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c4c(cc[n+]3[O-])CN(C)C4=O)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (204 mg, 0.381 mmol) and 4-amino-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 5-oxide (Compound 310A, 68.3 mg, 0.381 mmol). The reaction mixture was concentrated under reduced pressure to yield a dark yellow oil which was purified by silica gel chromatography on the combi-flash Rf system using DCM/MeOH (100:0→90:10). The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (38.4 mg, 17%). 1H NMR (DMSO-d6, 400 MHz): δ=8.99 (br. s., 1H), 8.47-8.55 (m, 3H), 7.47 (d, J=6.57 Hz, 1H), 7.24 (d, J=7.58 Hz, 1H), 6.85 (s, 1H), 6.56 (d, J=8.08 Hz, 1H), 4.45 (s, 2H), 3.90-3.99 (m, 4H), 3.70 (s, 3H), 3.12-3.21 (m, 2H), 2.86-2.89 (m, 3H), 1.17 (t, J=7.07 Hz, 6H). MS (ES+): m/z 597.10 [MH+] (TOF, polar).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:23][C:18]1[CH:19]=[C:20]([O:14][CH:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[C:10]([F:12])([F:13])[F:11])[N:21]=[C:16]([NH2:15])[N:17]=1
Reactant: OC(C1CCCCC1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(C2CCCCC2)C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 65.2 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to the solution of 1-cyclohexyl-2,2,2-trifluoro-ethanol (182 mg, 1 mmol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 202 mg of 4-chloro-6-[1-cyclohexyl-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine, yield 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:18]([C:17]2[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=2[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCCc2ccc(Cl)cc21

Procedure:
Prepared in analogy to example 1.1 from 7-chloro-1,2,3,4-tetrahydro-quinoline (CA [90562-35-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3[CH:13]=[CH:14][CH2:15][S:16][C:6]=3[C:5]=2[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:21]([SH:23])[CH3:22].Cl>C(Cl)Cl>[CH2:21]([S:23][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3[CH:13]=[CH:14][CH2:15][S:16][C:6]=3[C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCS
Reactant: COc1ccc2c(c1)c1c(n2C)C=CCS1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCSc1ccc2c(c1)c1c(n2C)C=CCS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
500 mg (1.9 mmol) of the compound obtained in Example 24, predissolved in 5cm3 of methylene chloride distilled over phosphorus pentoxide are added dropwise to a mixture, cooled to 0° C., of 380 mg (2.84 mmol)of aluminum chloride and 2.3 g (37.9 mmol) of ethanethiol. After stirring at 0° C. for 1 h, 1.5 eq. of aluminum chloride and 20 eq. of ethanethiol are added again. The mixture is stirred again for 1 h at 0° C. and then poured onto ice, treated with 1N hydrochloric acid and then extracted with dichloromethane. After treatment of the organic phase and purification of the crude product by chromatography on a silica column the expected compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc(CCCC(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc(CCCC(=O)OCc2ccccc2)n1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a stirred solution of 60.0 g (236 mmol) of 4-[1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]butanoic acid from step C in 400 mL of DMF was added 48.9 g (354 mmol) of potassium carbonate followed by dropwise addition of 40.0 mL (300 mmol) of benzyl bromide. The resulting mixture was stirred for 24 h, quenched with water, and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed (Brine), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 30% EtOAc in hexanes to afford the title compound as a yellow oil (55.6 g. 68.4%). LC-MS: m/z (ES) 345 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (320 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.1 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (330 mg, 1.1 mmol, Amine-49, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:13])#[N:2].[SH2:14].[Na].Cl.C(N(CC)CC)C>O1CCOCC1.O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:13])=[S:14]
Reactant: S
Reactant: COC(=O)c1ccc(C#N)c(C)c1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(N)=S)c(C)c1
Temperature: 55 °C

Procedure:
To a solution of methyl 4-cyano-3-methylbenzoate (36 mg, 0.205 mmol) in 1,4-dioxane (0.5 mL) and water (0.500 mL), was added sodium hydrogen sulfide (0.019 mL, 0.616 mmol) and triethylamine hydrochloride (170 mg, 1.233 mmol). The reaction mixture was heated at 55° C. overnight. The reaction was allowed to cool and water was added. The mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo to give the product as a yellow solid. LCMS calc.=210.1; found=210.2 (M+1)+. 1H NMR (500 MHz, CDCl3) 7.86 (s, 1H); 7.84 (d, J=8.1 Hz, 1H); 7.42 (d, J=7.9 Hz, 1H); 7.16 (s, 2H); 3.93 (s, 3H); 2.51 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][CH:14]=O)[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20].[C:22]1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:22])[N:17]([CH2:18][CH:19]([OH:21])[CH3:20])[C:9]=32)=[CH:5][CH:4]=1
Reactant: CC(O)CN
Reactant: Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(cc(C)n1CC(C)O)C2
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A solution of 1.8 g of (RS)-6-methoxy-2-(2-oxoethyl)-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.48 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 90 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.37 g (65%) of (RS)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown solid which was used directly in the next reaction.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH2:4]1
Reactant: Clc1ccc(Br)nc1
Reactant: O=C1NCC(CCl)O1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C1OC(CCl)CN1c1ccc(Cl)cn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
A mixture of 5-(chloromethyl)-1,3-oxazolidin-2-one (136 mg), 2-bromo-5-chloropyridine (192 mg), cesium carbonate (489 mg), bispalladium tribenzylideneacetone (137 mg) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (260 mg) in 1 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (5×10 ml) eluting with ethyl acetate (50 ml). The eluent was concentrated in vacuo to provide a clear reddish-brown liquid, which was purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 4 column volumes to provide the title compound (204 mg, 83%). Mass spectrum (ESI) 249.0 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.28 (d, J=2.5 Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.68 (dd, J=9.0, 2.6 Hz, 1H), 4.90 (m, 1H), 4.35 (dd, J=8.9, 11.0 Hz, 1H), 4.17 (dd, J=5.7, 10.8 Hz, 1H), 3.78 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: O=Cc1ccc(B(O)O)cc1
Product: COc1cc(Nc2cncc(-c3ccc(C=O)cc3)n2)cc(OC)c1OC
Yield: 61.6 %

Procedure:
Using Method C with 200 mg (0.68 mmol) 2a and 123 mg (0.82 mmol) 4-formylphenylboronic acid, 153 mg (61.7%) pure title compound were obtained after preparative HPLC (eluent: AcOEt) purification of the whole batch. Reaction time: 24 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.64 (s, 3H, CH3O(4′)), 3.83 (s, 6H, CH3O(3′+5′)), 7.25 (s, 2H, Harom(2+6)), 8.05 (d, 2H, Harom 2′+6′, J=8.22), 8.23 (s, 1H, HP5), 8.35 (d, 2H, Harom3′+5′), 8.64 (s, 1H, HP3), 9.68 (s, 1H, NHamine), 10.08 (s, 1H, CHO); MS, (C20H19N3O4), m/z: 395 [M++1, 100].
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][CH2:16][O:17][C:18]([CH:20]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19].[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[CH3:15][CH2:16][O:17][C:18]([CH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19]
Reactant: CCOC(=O)C1CCC(C=O)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC(CNCC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Yield: 47.1 %

Procedure:
Sodium triacetoxyborohydride (2.08 g, 9.86 mmol) was added to a solution of 5-formyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (891 mg, 3.29 mmol) and glycine t-butyl ester (1.65 g, 9.86 mmol) in dichloromethane (20 mL) over 2 minutes—a small amount of gas evolution was observed. After 1 hour the reaction was quenched with saturated ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography with methanol and dichloromethane as the eluant at a gradient of 0-10%. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (601 mg, 1.55 mmol, 47%). C19H34N2O6 calculated 386.2, observed [M+1]+ 387.2; rt=1.61 min.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH3:11].C[Si]([C:16]#[N:17])(C)C>CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH2:11][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[CH3:10])[C:16]#[N:17]
Reactant: Cc1c(F)cccc1C=O
Reactant: C[Si](C)(C)C#N
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: Cc1c(F)cccc1C(N)C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-fluoro-2-methyl-benzaldehyde (5.0 g) in methanol (20 ml) were added sequentially ammonia solution (40.5 ml, 7 M solution in methanol) and tetraisopropyl orthotitanate (12.6 ml) and the resulting mixture was stirred at r.t. for 1 h. Trimethylsilylcyanide (4.69 ml) was then added dropwise and stirring continued at r.t. overnight. The reaction mixture was poured onto ice-water (400 ml) and the mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with brine and then dried over sodium sulphate and concentrated in vacuo to afford (RS)-amino-(3-fluoro-2-methyl-phenyl)-acetonitrile (5.90 g, quant.) as an orange solid. 1H NMR δ (CDCl3, 300 MHz): 7.39 (1H, d, J=7.3 Hz), 7.31 (1H, m), 7.17 (1H, dd, J=9.6 & 9.6 Hz), 5.16 (1H, t, J=7.8 Hz), 5.16 (1H, d, J=7.8 Hz), 2.26 (1H, d, J=2.1 Hz).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:6]([CH3:20])[CH:5]=1.[Li+].[OH-]>C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[CH3:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(C)c(CCC(=O)OC(C)(C)C)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid methyl ester (10.8 g, 37.0 mmol) in ethanol (100 mL) a 2 M aq. solution of LiOH (50 mL) is added at 0° C. The turbid mixture is stirred at 0° C. for 30 min, then at rt for 4 h. The mixture is diluted with 10% aq. citric acid solution and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The solid residue is suspended in diethyl ether/heptane, stirred at rt, and filtered. The slurry procedure in diethyl ether/heptane is repeated. The solid material is collected and dried under HV to give 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid (5.09 g) as a white crystalline powder; LC-MS: tR=0.95 min, [M+1]+=279.14; 1H NMR (CDCl3): δ1.47 (s, 9H), 2.30-2.40 (m, 2H), 2.39 (s, 6H), 2.94-3.03 (m, 2H), 7.75 (s, 2H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][N:19]([S:35]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)(=[O:37])=[O:36])[CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccs1)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
7-(3-Piperidin-1-yl-propoxy)-2-(thiophene-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and thiophene-2-sulfonyl chloride (114 mg, 0.63 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (160 mg, 76% yld). MS(ES+)421.1(M+H)+.