Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]C=3)C[C@@H:13]2O)=[N:5]C(CC)=CN=1)C.Br[C:23]1[C:28]([CH2:29][CH3:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])=[C:25]([CH2:39][CH3:40])[N:24]=1.C(C1C(N)=NC(C)=CC=1)C>>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:26]1[N:27]=[C:28]([CH2:29][CH3:30])[C:23]([NH:5][C:4]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:20]=[C:12]([CH3:13])[N:11]=2)=[N:24][C:25]=1[CH2:39][CH3:40]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Agent: CCc1ccc(C)nc1N
Product: CCc1ccc(C)nc1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and 3-ethyl-6-methylpyridin-2-amine, and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ 0.95, 1.15, 2.33, 2.31, 2.51, 2.70, 6.95, 7.51, 7.75, 8.57; HRMS (ESI+) calcd for C22H24Cl2N4 (M+H)+ 415.1456, found 415.1442.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN1CCN(CCCO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Di-tert-butyl azodicarboxylate (0.478 g, 2.08 mmol) was added portionwise to a mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.350 g, 1.66 mmol), 3-(4-methyl-piperazin-1-yl)-propan-1-ol (Intermediate 9, 0.276 g, 1.74 mmol), and triphenylphosphine (0.544 g, 2.08 mmol) in dichloromethane (20 mL) at r.t. If necessary, further alcohol was added. After stirring for 2 h, the solution was concentrated to 10 mL, mounted on silica and chromatographed (gradient, dichloromethane to dichloromethane:methol=3.2 within 1 h) to obtain 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (brownish solid, 0.431 g, 1.23 mmol, 74%). LC/ESI-MS: m/z=351 [M(35Cl)+H]+; Rt=1.88 min Cf. also WO 04/143472, page 32,
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>[Pd].C1(C)C=CC=CC=1>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH:24][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCN(CC)CCN
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4′-(trifluoromethyl)-4-biphenylcarbaldehyde, (43.6 kg, 1.1 eq., see WO 01/60805), N,N-diethylethylenediamine (21.2 kg, 1.15 equiv.) and 5% palladium on charcoal (Degussa E101 N/W, 50% wet paste, 1.7 kg) in toluene (138 Kg) was hydrogenated at 20±3° C. and 50 psi until completion. The reaction mixture was filtered and the catalyst bed washed with toluene (2×36.7 kg). The solution was washed with water (84.8 kg) and concentrated under reduced pressure to ca. 85 L. This concentrate was used in the next step, Example 6, without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](N(CC)CC)C.ClCOC=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=COCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
To a solution of 8.8 g(0.0344 mol) of N-t-butoxycarbonylphenylalanine in 50ml of dichloromethane were successively added 5.25 ml of triethylamine solution, and 3 ml of chloromethylformate at 0° C. 50 mg of 4-dimethylaminopyridine was added to catalyze the reaction. After the reaction was completed the reaction mixture was extracted with dichloromethane and distilled under a reduced pressure to give the title compound quantitatively.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:17]=[N:18][C:19]([C:20]([O:22]CC)=[O:21])=[C:5]2[C@@H:4]2[CH2:25][CH2:26][N:3]12.[OH-].[Na+].C(O)C.Cl>O>[O:1]=[C:2]1[C:8]2[C:9]([C:13]([F:16])([F:14])[F:15])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:17]=[N:18][C:19]([C:20]([OH:22])=[O:21])=[C:5]2[C@@H:4]2[CH2:25][CH2:26][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F

Procedure:
A mixture of 4.44 g (12.2 mmol) of ethyl (S)-12,12a-dihydro-9-oxo-8-(trifluoromethyl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 0.556 g (13.9 mmol) of sodium hydroxide, 18 ml of ethanol and 9 ml of water is heated to boiling under reflux for 1 hour. The ethanol is then distilled off in vacuo and the residue is diluted with 25 ml of water. The mixture is neutralized by the addition of 13.9 ml (13.9 mmol) of 1N hydrochloric acid, the mixture is cooled to about 0°, the product is filtered off under suction, rinsed with water and dried at 90° in a high vacuum. There is obtained (S)-12,12a-dihydro-9-oxo-8-(trifluoromethyl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of decomposition point 227°-228°.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[N:3][C:2]=1[CH:10]=O.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([OH:35])=[C:29]([CH2:36][CH3:37])[CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([OH:35])=[C:29]([CH2:36][CH3:37])[CH:28]=3)[O:22][C:21](=[O:23])[C:20]([CH2:10][C:2]3[N:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[C:19]([OH:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Reactant: O=Cc1nc2ncccn2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncccn4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where [1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.20 (t, J=2.56 Hz, 6H), 1.30–1.80 (brm, 6H), 2.00–2.18 (brm, 5H), 2.40 (q, J=20.06 Hz 4H), 2.80 (m, 4H), 3.45 (m, 3H), 6.70 (s, 2H), 7.17 (d, J=2.54 Hz, 1H), 8.80 (m, 2H), 9.29 (s, 1H). Anal. Calcd. For C28H34O4N4, C, 68.55; H, 6.99, N, 11.42. Found: C, 68.80; H, 7.31; N, 11.45.
Reaction SMILES: O[C:2]1[C:7](=[O:8])[C:6]([CH3:10])([CH3:9])[C:5](=[O:11])[C:4](=[CH:12][CH:13]=[C:14]2[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[C:16]([OH:24])=[CH:15]2)[CH:3]=1.S([O:30][CH3:31])(OC)(=O)=O.[C:32](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C>[CH3:32][O:24][C:16]1[C:17](=[O:23])[C:18]([CH3:22])([CH3:21])[C:19](=[O:20])[C:14](=[CH:13][CH:12]=[C:4]2[C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[C:7](=[O:8])[C:2]([O:30][CH3:31])=[CH:3]2)[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C(=O)C(O)=CC(=CC=C2C=C(O)C(=O)C(C)(C)C2=O)C1=O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: COC1=CC(=CC=C2C=C(OC)C(=O)C(C)(C)C2=O)C(=O)C(C)(C)C1=O

Procedure:
4 g of bis(3-hydroxy-5,5-dimethyl-4,6-dioxocyclohex-2-enylidene)ethane (from Example 3) were dissolved in a mixture of 240 ml of dioxane and 240 ml of acetonitrile by refluxing under nitrogen. 16 g of dimethyl sulfate were then added, followed by 12 g of finely crushed anhydrous potassium carbonate. The batch turned greenish blue at once, but became yellow in the course of an hour of heating under reflux. The reaction mixture was filtered while still hot, the filter cake was washed with acetonitrile, and the combined organic phases were concentrated in a rotary evaporator. The residues of alkylating agent were removed by digestion with ether, and the insolubles were removed by heating in chloroform. The filtrate was concentrated and the residue was repeatedly recrystallized from acetone. This gave a solid in the form of reddish yellow prisms.
Reaction SMILES: [Se](=O)=[O:2].CC([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)=O.[O:15]1[CH2:20][CH2:19][O:18]CC1>>[Cl:13][C:11]1[CH:12]=[C:7]([C:19](=[O:18])[C:20]([OH:15])=[O:2])[CH:8]=[C:9]([Cl:14])[CH:10]=1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: C1COCCO1
Reactant: O=[Se]=O
Product: O=C(O)C(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C

Procedure:
Selenium dioxide (30.0 g 270 mmol) was dissolved in dioxane (450 mL) and warmed to 50° C. 3,5-Dichloroacetophenone (30.0 g, 158 mmol) was added at at this temperature and the resulting mixture was refluxed for 4 h. After completion of the reaction, the mixture was filtered through celite and concentrated in vacuo. (3,5-Dichlorophenyl)(oxo)acetic acid was isolated and purified by column chromatography, eluting with ethyl acetate/hexane mixtures (28 g, 80%).
Reaction SMILES: [Na+:1].N[C@H:3]1[C@@H:6]([CH2:7][O:8][C:9](=[O:11])[NH2:10])[N:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:4]1=[O:16]>CC(C)=O.O>[Na+:1].[C:9]([O:8][CH2:7][CH:6]1[N:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:4](=[O:16])[CH2:3]1)(=[O:11])[NH2:10]
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)OCC1CC(=O)N1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.62 g (6.20 mmol) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 180 ml of acetone/water (2:1) and the solution is treated with 3.27 g (6.83 mmol) of (Z)-2-(2-amino-4-thiazolyl)-2-[[1-[t-butoxycarbonyl]-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl thioester. The mixture is stirred at room temperature for 12 hours. A further 60 mg (0.12 mmol) of the aforementioned thioester are added thereto and the stirring is continued for a further 3 hours. Acetone is removed under reduced pressure and 50 ml of water are added thereto. The crystals obtained are filtered off and washed with water. The mother liquor is partially evaporated (37° C., 15 mmHg) and chromatographed (MCI gel, water). After lyophilization, there are obtained 2.28 g (77%) of (3S,4S)-3-[2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino] acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13].CN(C)[CH:18]=[O:19].O>O1CCCC1>[F:15][C:10]1[CH:9]=[CH:8][C:7]([CH:18]=[O:19])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iso-propyl magnesium bromide (18 ml, 1M in tetrahydrofuran, 18 mmol) was added dropwise to an ice-cooled solution of 5-bromo-2-fluorobenzonitrile (3 g, 15.1 mmol) in tetrahydrofuran (25 ml), and once addition was complete, the mixture was allowed to warm to room temperature and stirred for a further 2 hours. N,N-Dimethylformamide (3.5 ml, 45.2 mmol) was added and the reaction stirred for 3 hours. Water was added and the mixture extracted with ethyl acetate (3×). The combined organic extracts were washed with 6% aqueous magnesium sulphate solution, and brine, then dried (Na2SO4) and concentrated under reduced pressure. The product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:hexane (10:90 to 20:80) to afford the title compound as a light yellow solid, 1.01 g.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22](O)=[O:23])=[CH:21][N:16]2[CH:15]=1>>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[O:23])=[CH:21][N:16]2[CH:15]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using 3-(trifluoromethoxy)aniline and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:13]([CH:14]=[CH2:15])=[CH:12][C:9]([CH2:10][NH2:11])=[C:8]([O:16][CH3:17])[CH:7]=1)(=[O:4])=[O:3].Cl.FC(F)(F)C(O)=O.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl.C(N(CC)CC)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([CH:36]=[CH:37][C:38]([NH:11][CH2:10][C:9]2[CH:12]=[C:13]([CH:14]=[CH2:15])[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=2[O:16][CH3:17])=[O:39])=[CH:34][CH:35]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Reactant: C=Cc1cc(CN)c(OC)cc1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)c(OC)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 19 %

Procedure:
To a ice-cooled solution of 4-methanesulfonylamino-2-methoxy-5-vinyl-benzylamine and HCl salt (220 mg, 0.73 mmol) prepared in the synthesis of Example 48 in methylene chloride was treated with trifluoroacetic acid (100 mg, 0.88 mmol)) for 1 hr, and then concentrated under reduced pressure. The part of the crude residue (50 mg, 0.13 mmol) was suspended in methylene chloride and treated with triethylamine followed by 3-(4-tert-butyl-phenyl)-acrylic acid (30 mg) and DMTMM (40 mg). The resulting mixture was stirred for 2 days at ambient temperature and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=3/2) to yield a white solid (11 mg, 19%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)=[O:4].[C:14]([C:17]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])[NH2:15].C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[C:14]([C:17]([C@@H:30]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:12][CH2:11][CH2:10][C:9]=3[CH:13]=2)=[O:4])[CH2:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])[NH2:15]
Reactant: O=C(CCl)c1ccc2c(c1)CCO2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cl
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CC(=O)c2ccc3c(c2)CCO3)C1

Procedure:
A mixture of 5-chloroacetyl-2,3-dihydrobenzofuran (176.2 g-see Preparation 18), 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (335.0 g-see Preparation 10(B)) and potassium carbonate (335 g) were stirred in industrial methylated spirits at room temperature for 18 hours then concentrated in vacuo. The oily solid was partitioned between methylene chloride (2,500 ml) and water (2,500 ml) and the organic phase was concentrated to an oil in vacuo. The oil was dissolved in ethyl acetate (3,350 ml) and acidified with hydrochloric acid dissolved in isopropyl alcohol (180.6 ml at 24% w/v). Filtration produced the title compound as a hygroscopic solid, yield 467 g.
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.[BrH:40]>CC(O)=O.C(Cl)Cl>[C:16]([O:15][C@@H:9]1[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=3)[CH:24]=2)[O:6][C@@H:5]([Br:40])[C@H:10]1[O:11][C:12](=[O:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: Br
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@@H](Br)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reaction time: 0.5 h

Procedure:
The tetraacetate of step A (8.08 g, 14.4 mmol) was treated with 33% HBr in AcOH (30 ml) for 1 hour. The reaction was diluted with CH2Cl2 (60 ml), stirred for 30 minutes, diluted with more DCM, washed 3× with ice cold H2O and with sat. aq. NaHCO3 (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum to give acetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20](O)=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][C@@H:40]([NH:48][C:20]([C:8]1[C:9]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[NH:19][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid G2 (0.087 mmol) in DMF (1 mL), DIEA (0.26 mmol) and ((S)-2-amino-3-phenyl-propyl) -carbamic acid tert-butyl ester (0.13 mmol) were added. The mixture was cooled to 0° C., EDCI hydrochloride (0.13 mmol) and HOBT (0.13 mmol) were added and stirring was kept overnight at rt. The suspension was filtered and the solid was washed with aq saturated NaHCO3 and with water. After drying, the title compound was isolated in 43% yield. ESI (+) MS: m/z 521 (MH+). 1H NMR: 1.40 (s, 9H) 2.80-2.89 (m, 1H) 3.00-3.11 (m, 2H) 3.12-3.21 (m, 1H) 4.18-4.30 (m, 1H) 6.91-6.97 (m, 1H) 7.00-7.06 (m, 1H) 7.16-7.23 (m, 1H) 7.25-7.34 (m, 4H) 7.37-7.43 (m, 1H) 7.49-7.56 (m, 2H) 7.88 (d, J=7.62, 2H) 8.00 (d, J=9.00, 1H) 8.31 (d, J=9.00, 1H) 8.72 (s, 2H) 9.51 (s, 1H) 11.72 (bs, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][C@H:8]([OH:10])[CH2:7][CH2:6][N:5]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].I[CH3:20].O>CN(C=O)C>[CH3:20][O:10][C@@H:8]1[CH2:7][CH2:6][N:5]([C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[C@H:4]([CH3:3])[CH2:9]1
Reactant: CI
Reactant: C[C@@H]1C[C@H](O)CCN1[C@H](C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H]1CCN([C@H](C)c2ccccc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (710 mg, 17.7 mmol; 60% dispersion in mineral oil) was added to a solution of (2R,4R)-2-methyl-1-((R)-1-phenylethyl)piperidin-4-ol (1.95 g, 8.87 mmol) in DMF (47 mL) at 0° C. After 15 min, iodomethane (666 μL, 10.7 mmol) was added and the solution was allowed to warm to room temperature. After 1 h, water was slowly added at 0° C. The aqueous phase was extracted with a 4:1 mixture of EtOAc/n-heptane (3×). The combined organic layers were washed with brine (3×), dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was purified via FCC (0-30% EtOAc/heptane) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (d, J=7.8 Hz, 2H), 7.35 (t, J=7.6 Hz, 2 H), 7.21-7.28 (m, 1 H), 4.33 (q, J=6.8 Hz, 1 H), 3.36 (s, 3 H), 3.11-3.22 (m, 1 H), 2.59-2.71 (m, 1 H), 2.49 (dt, J=11.9, 3.8 Hz, 1 H), 1.99-2.16 (m, 2 H), 1.85 (d, J=12.1 Hz, 1 H), 1.33-1.42 (m, 1 H), 1.28 (d, J=7.1 Hz, 4 H), 1.25 (d, J=6.3 Hz, 3 H); MS (ESI+) m/z 234.2 (M+H)+; [α]25D-49.17 (c 1.0, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sulfuric acid (108 mL) and 3-bromobenzaldehyde (25 g, 0.135 mol) were cooled to 0° C. in a flask. Potassium nitrate (14.3 g, 0.14 mol) was added to the resulting mixture, portion wise over 1 h. The resulting mixture was stirred an additional 2 h at 0° C. For work up, the resulting mixture was poured into 2 L of ice and then filtered to yield a solid. The solid was purified by silica chromatography (330 g, 30% Et2O/heptane) to yield a residue, which was recrystallized from EtOAc/heptane to yield a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[Cl:30]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:30])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)cc2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 106.4 %

Procedure:
To a solution of 3-[4-(3-methoxy-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (226 mg, 0.57 mmol) in isopropanol (2 mL) was added N-chlorosuccinimide (84 mg, 0.63 mmol) and 2 drops of dichloroacetic acid. The solution was heated at 60° C. for two hours. The solution was allowed to cool to room temperature and concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as a light yellow semi-solid (260 mg, quantitative yield). MS (M+H): 429
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-chloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=596.1)=70%.