Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Cl:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([OH:24])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([O:24][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=2[CH3:12])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)c2c1CCCC2
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Temperature: 140 °C
Yield: 55.2 %

Procedure:
To a solution of 35.62 g (0.19 mole) of 4-chloro-3,5-dimethyl-1-nitrobenzene and 38.54 g (0.21 mole) of 4-chloro-5,6,7,8-tetrahydro-1-naphthol in 300 mL of dry DMF under an atmosphere of nitrogen and at room temperature was added 29.16 g (0.21 mole) of anhydrous potassium carbonate. The resulting reaction mixture was heated to 140° C. (internal). The reaction mixture was then heated between 140° and 150° C. for 40 hrs. The reaction mixture was then cooled to room temperature. The DMF was removed on a rotary evaporator in vacuo. The remaining dark brown semi-solid was dissolved in 500 mL of hot toluene and filtered. The collected solids were thoroughly washed with hot toluene. The toluene washings were combined with the toluene filtrate and the solvents removed to afford 34.8 g of dark brown solid. Recrystallization from hot hexane containing a little ethylene acetate along with the use of decolorizing carbon afforded 22.04 g of pale yellow solid; m.p. 176° -179° C. NMR (CDCl3): δ1.7-2.0 (m, 4H), 2.20 (S, 6H), 2.7-3.0 (m, 4H), 5.95 (d, J=9 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 8.02 (S, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[OH:14][C:15]1[C:10]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:11]=2)[N:9]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)Oc1ccc(N)cc1
Product: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1O

Procedure:
Prepared as in Example 1c from 4-isopropoxyaniline and diethyl 2-(ethoxymethylene)malonate as a yellow solid (20%). MS 276 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[C:17]3[C:12](=[C:13]([O:20]C)[C:14]([O:18]C)=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([O:22]C)=[C:4]([O:24]C)[CH:3]=1.B(Br)(Br)[Br:27].ClCCl.CO>ClCCl>[BrH:27].[F:1][C:2]1[C:7]([CH:8]2[C:17]3[C:12](=[C:13]([OH:20])[C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([OH:22])=[C:4]([OH:24])[CH:3]=1
Reactant: COc1cc(F)c(C2CNCc3c2ccc(OC)c3OC)cc1OC
Reactant: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Oc1cc(F)c(C2CNCc3c2ccc(O)c3O)cc1O

Procedure:
0.09 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline was dissolved in 25 ml of dichloromethane; and to the mixture was added dropwise 1M boron tribromide-dichloromethane solution (27 ml) under an argon gas stream, at internal temperature -30° to -60° C. under cooling while stirring, The mixture was stirred for 3 hours at room temperature and 7.0 ml of methanol was added to the mixture under cooling with dry ice-methanol bath, dropwise. The mixture was stirred for 30 minutes at room temperature, the crystals which separated out was collected, giving 0.75 g of 4-(6-fluoro-3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([C:31]3[CH:35]=[CH:34][O:33][CH:32]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:36]C1C=CC(C([O-])=O)=C(CS(C2C=CC=CC=2)(=O)=O)C=1C1C=COC=1>>[C:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][O:20][C:15]1[C:14]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][C:4]([F:36])=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([OH:19])=[O:18])=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: O=C([O-])c1ccc(F)c(-c2ccoc2)c1CS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Product: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccc(F)cc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 6, starting from methyl 2-[2-(t-butoxycarbonyl)aminoethoxy]-6-(4-fluorobenzenesulphonylmethyl-3-(furan-3-yl)benzoate (Intermediate 13).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O)(=O)C>CC(O)C>[C:15]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:32])[NH:22][C:18]=1[CH3:19])#[N:16]
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OC(C)(C)C)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 55.8 mg (0.53 mmol) of sodium 1-cyanoprop-1-en-2-olate, 83.5 mg (0.53 mmol) of tert-butyl 3-amino-crotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 89 mg (42% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:2]=1.CN(C)C=O.[Cl:24]CCCl>S(Cl)(Cl)=O>[ClH:24].[Cl:24][C:16]([C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:18]
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CCCC2
Reactant: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1cc(-c2cccnc2)n2c1CCCC2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A solution of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid (13.3 g) in a mixture of thionyl chloride (19.2 cc), dimethylformamide (0.05 cc) and 1,2-dichloroethane (160 cc) is heated to a temperature of about 70° C. The suspension obtained is kept at a temperature of about 70° C. for 3 hours. The reaction mixture is cooled to a temperature of about 20° C. and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. The residue is suspended in cyclohexane (300 cc) and the solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. The same operation is repeated twice. 1-Chloroformyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine hydrochloride (16.3 g) is thus obtained in the form of light green crystals melting at 205° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)[CH3:15].Cl>CS(C)=O.CCOCC>[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CCOC(CBr)OCC
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(COc1ccc(CC(=O)O)cc1)OCC
Yield: 93.9 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid (50.0 gm, 0.33 mol) in DMSO (300 mL) was added 50% aqueous NaOH (57.0 gm, 0.71 mol) with stirring. After stirring for 10 min at room temperature bromoacetaldehyde diethyl acetal (66.0 gm, 0.33 mol) was added. The solution was heated at 100°-110° C. for 2 hr when an additional 2 gm of 50% NaOH was added. After heating for another hour the reaction mixture was cooled and poured into a mixture of aqueous HCl (30 mL of conc. HCl in 400 mL ice-H2O) and Et2O. The layers were separated and hexane was added to the Et2O layer. The organic layer was washed successively with H2O (twice) and saturated NaCl before being dried over Na2SO4, filtered and evaporated to dryness to give 83.7 gm (0.31 mol) of 4-[(2,2-diethoxy)ethoxy]phenylacetic acid which was suitable for use in the next step.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)Cl.[O-2].[Mn+2].O=[Mn]=O>[N:1]1([C:7]2[C:8]3[N:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1ccc2ncnc(N3CCCCC3)c2n1
Agent: O=[Mn]=O
Agent: [Mn+2]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc2ncnc(N3CCCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
[4-(1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methanol (Intermediate 1.6) (3.95 g; 16.2 mmol; 1.00 eq.) was dissolved in DCM (160 mL). The solution was cooled down to 0° C. and manganese oxide (16.5 g; 0.162 mol; 10 eq.) was added. The reaction was stirred 5 min at 0° C. then overnight at rt. To complete the conversion, MnO2 was added after 12 hours and 20 hours (two batches of 4.96 g; 48.48 mmol; 3 eq.). After 20 hours, the reaction was complete. MeOH (100 mL) was added and the mixture was filtered through Celite, and widely rinsed with DCM/MeOH 1:1 mixture. Solvents were removed under reduced pressure to give 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 1.7). This product was used in the next step without further purification. Amount: 4.1 g; Formula: C13H14ON4; HPLC Purity: 58.84%; LC-MS: M/Z ESI: Rt (min) 1.53; 243.06 (M+1); HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=1.39; 58.84. 1H NMR (DMSO-d6) δ 9.95 (s, 1H), 8.52 (s, 1H), 8.16 (m, 2H), 4.46 (1, 4H), 1.70 (1, 6H).
Reaction SMILES: C([O:4][CH:5]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C>[OH-].[K+]>[CH3:22][N:20]([CH3:21])[CH2:19][CH:5]([OH:4])[CH:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(CN(C)C)C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 99 %

Procedure:
2-Acetoxy-3-dimethylamino-1,1-diphenyl-propane (200mg) was dissolved in methanolic potassium hydroxide (5% 10 ml) and the solution allowed to stand overnight. Solvent was evaporated and the residue dissolved in ether and water. The ether extract was dried and evaporated to give 3-dimethylamino-1,1-diphenyl-propan-2-ol (170 mg, 97%), m.p. 72° - 73°
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)C(C)C)(C)C.CS([C:33]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:36]=[CH:35][N:34]=1)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[C:33]2[N:38]=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)[CH:36]=[CH:35][N:34]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 17.4 %

Procedure:
To a mixture of ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (652 mg, 2.46 mmol) and N,N-diisopropylethylamine (570 μL, 3.28 mmol) was added 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (495 mg, 1.64 mmol) and the resultant mixture heated at 100° C. for 16 h in a reactivial. The cooled reaction mixture was diluted with CH2Cl2 (30 mL), washed with water (20 mL), the aqueous extracted with CH2Cl2 (30 mL) and the CH2Cl2 extracts combined and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluted with cyclohexane:EtOAc 10:1 afforded the title compound as a colourless gum (139 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.Cl>CC(O)C>[ClH:12].[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: COc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1)N(c1ncnc3cc(OC)c(OC)cc13)CC2
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 91% yield from 6-methoxy-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to a procedure analogous to that given in Example 2. (M.P. 246°-247° C.(dec); LC-MS: 338 (MH+); anal. RP18-HPLC RT: 4.27 min.).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:30]=[CH:29][O:28][N:27]=1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:25][C:26]5[CH:30]=[CH:29][O:28][N:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CNc3ccon3)ccc1-2
Yield: 52 %

Procedure:
Following the procedure for 119, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and 3-amino-isoxazole were reacted. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) gave 284 as a white solid (154 mg, 52%). LCMS: RT=10.79 min, [M+H]+=409. 1H NMR δ (ppm) (CDCl3): 8.33 (1 H, d, J=8.10 Hz), 8.04 (1 H, d, J=1.68 Hz), 7.90 (1 H, s), 7.16 (1 H, d, J=8.19 Hz), 7.06 (1 H, s), 5.93-5.84 (1 H, m), 5.85-5.83 (1 H, m), 4.42 (2 H, s), 4.38 (2 H, t, J=5.02 Hz), 3.42-3.36 (2 H, m), 1.60 (6 H, d, J=6.62 Hz). 1 Exchangeable proton not seen.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2/[CH:13]=[CH:14]/[C:15]([NH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:26]=[CH:27][C:28]3[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:20]1)=[O:16].CS(N)(=O)=[O:38].CC(N(C)C)=O.CC(O)(C)C.[OH2:52]>>[OH:52][C@H:14]([C@@H:13]([OH:38])[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1)[C:15]([NH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:26]=[CH:27][C:28]3[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:20]1)=[O:16]
Reactant: CS(N)(=O)=O
Reactant: O
Reactant: COc1ccc2nccc(/C=C/C(=O)NC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Solvent: CC(=O)N(C)C
Solvent: CC(C)(C)O
Product: COc1ccc2nccc([C@H](O)[C@@H](O)C(=O)NC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of the compound of Example 4 (0.08 g, 0.16 mmol), methanesulfonamide (0.017 g) and AD-mix α (0.7 g) in t-BuOH/H2O (5 mL/5 mL) was vigorously stirred at rt overnight. DMA (0.5 mL) added and stirring continued for 5 h. The reaction was carefully quenched by the portionwise addition of sodium bisulfite (1 g). The phases were separated and the aq. phase extracted with EA. The combined org. layers were dried over MgSO4 and concentrated. Chromatography on SiO2 (EA/MeOH 9:1, 4:1, +1% NH4OH) followed by trituration with ether/MeOH gave the desired product as a colourless solid (0.022 g, 26% yield).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19]O)=[CH:11][N:10]=1.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>ClCCl>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][Cl:23])=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1nc(N[C@@H]2C[C@H]3CC[C@@H]2C3)ncc1CCl
Temperature: 25 °C

Procedure:
To a mixture of rac-{2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (1.05 g) and dichloromethane (21 mL) was added thionyl chloride (0.8 mL) under ice-cooling, followed by stirring under ice-cooling for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, followed by stirring for 10 minutes. The reaction mixture was extracted with chloroform and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (1.06 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:2].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>C(O)C.Cl.C(O)(C)C.O>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH2:9][CH2:22][C:21]2[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=2)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:2]
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1C
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1C
Reaction time: 18 h
Yield: 27.6 %

Procedure:
A solution of 1-(5-ethyl-4-o-tolyl-thiophen-2-yl)-ethanone (51 mg, 0.209 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (47 mg, 0.172 mmol) in ethanol (1.5 mL) and 5 N HCl in isopropanol (0.7 mL) is stirred at it for 18 h. The solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (3 mL) and THF (3 mL) and treated with Pd/C (10 mg, 10% Pd). The slurry is stirred under 1.5 bar of H2 for 18 h. The mixture is filtered, the solvent of the filtrate is removed in vacuo and the crude product is purified on prep. TLC plates with heptane:EA 3:1 to give 1-(5-ethyl-4-o-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (18 mg) as a colourless oil; LC-MS: tR=1.12 min, [M+1]+=379.24.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:41])[CH3:42])[NH:17][C@H:16]2[C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:44])=[O:5])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (26 mg, 0.411 mmol) was treated with 50% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 250 mg. The solid was resolved on a Berger SFC system on a Whelk column under 100 bar, 30° C., and 45% of methanol to give two peaks: Peak 1, undesired enantiomer, 78 mg; Peak 2, 77 mg as white solid.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1)=[C:3]([Cl:5])[Cl:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH3:13][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([C:2]([Cl:1])=[C:3]([Cl:5])[Cl:4])[CH:7]=1)[CH2:12][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Yield: 60.8 %

Procedure:
To a refluxing solution of 5-(trichlorovinyl)-m-xylene (32.28 g) and dibenzoyl peroxide (3.43 g) in 1300 ml of benzene, N-bromosuccinimide (30.21 g) was added in portions. The resulting mixture was heated at reflux for 30 minutes at which point no N-bromosuccinimide was evident. The reaction mixture was concentrated under reduced pressure and the residue triturated with 250 ml of hexane. The precipitated succinimide was collected by filtration and thoroughly washed with hexane. The filtrate was concentrated and the residue chromatographed on silica (petroleum ether) to give 26.2 g of the desired benzyl bromide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1nccnc1C
Reactant: OO
Solvent: CC(=O)O
Product: Cc1ncc[n+]([O-])c1C
Temperature: 35 °C
Reaction time: 48 h
Yield: 94.6 %

Procedure:
A mixture of 2,3-dimethylpyrazine (L1) (25 g, 0.23 mol) and 30% H2O2 (52.4 g, 0.46 mol) in acetic acid (74 mL) was stirred for two days at 35° C. The solvent was removed under vacuum. Water was added and the mixture evaporated again. The residue was basified with aqueous K2CO3 and extracted with EtOAc. The organic phases were dried over Na2SO4 and concentrated. The resulting solid combined from two batches was recrystallized from cyclohexane to give 2,3-dimethylpyrazine 1-oxide (L2) (27 g). 1HNMR (CDCl3, 300 MHz) δ 8.18 (d, J=3.9 Hz, 1H), 8.02 (d, J=4.2 Hz, 1H), 2.58 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])(=[O:18])=[O:19]
Reactant: COC(CN)OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,2-dimethoxyethylamine (2.61 g) in methylene chloride (100 ml) were added 2-nitrophenylsulfonylchloride (5.0 g) and diisopropylethylamine (5 ml) dropwise at −78° C. and the mixture was stirred for 10 minutes at room temperature. To the reaction mixture was added 1N hydrochloric acid and was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and was concentrated to give the title compound having the following physical data.