Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:17]([Cl:20])([Cl:19])=[CH2:18]>C(Cl)Cl>[Cl:19][C:17]([Cl:20])=[CH:18][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[C:8]([F:12])[CH:7]=1)=[O:5]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH2Cl2 (25 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (7.9 g, 59.5 mmol) in CH2Cl2 (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one: (6.1 g, 90%) as a brown oil: 1H-NMR (d6-DMSO, 300 MHz) δ8.43 (d, 1H, J=8.4 Hz), 7.56 (s, 1H), Rf=0.76 (3:1 Hex:EtOAc).
Reaction SMILES: C(OC(=O)C(C)(C)CCCCC([N+]#C)S(C1C=CC(C)=CC=1)(=O)=O)C.I[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32]1.CC([O-])(C)C.[K+].[C:46]([O:50][C:51]([C:53]1([CH2:56][CH2:57][CH2:58][CH2:59][C:60](=[O:75])CCCCC2(C(OC(C)(C)C)=O)CC2)[CH2:55][CH2:54]1)=[O:52])(C)(C)[CH3:47]>Cl>[CH2:38]([O:37][C:35]([C:31]1([CH2:30][CH2:29][CH2:28][CH2:27][C:60](=[O:75])[CH2:59][CH2:58][CH2:57][CH2:56][C:53]([CH3:55])([CH3:54])[C:51]([O:50][CH2:46][CH3:47])=[O:52])[CH2:34][CH2:33][CH2:32]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)C1(CCCCI)CCC1
Reactant: CC(C)(C)OC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OC(C)(C)C)CC2)CC1
Agent: C#[N+]C(CCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Product: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC1(C(=O)OCC)CCC1

Procedure:
Compound 106e was prepared likewise Method C starting from 108a (11.01 g, 30.1 mmol), 105b (10.28 g, 33.1 mmol) and KOtBu (4.06 g, 36.2 mmol) to give, after purification by column chromatography (silica, heptane:EtOAc=6:1; a layer of NaHCO3 was put on the base of the column), ethyl 1-[11-ethoxy-5-isocyano-10,10-dimethyl-5-[(4-methylphenyl)sulfonyl]-11-oxoundecyl]-1-cyclobutanecarboxylate (14.11 g) as a colorless oil. Part of this oil (13.86 g, 25.3 mmol) was treated with cone aqueous HCl (50 mL), as described for 106d, to give crude 106e, which was stirred up in heptane (50 mL) and the resulting precipitate was filtered off and washed with heptane (3×50 mL). The combined filtrates were washed with aqueous NaOH (1M, 2×50 mL) and brine (50 mL) and dried to give 106e (9.44 g, >90% pure by 1H NMR, 75%) as a slightly yellow oil. 1H NMR: δ 4.12 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.50-2.29 (m, 2H), 2.37 (t, J=7.4 Hz, 4H), 1.95-1.70 (m, 6H), 1.61-1.44 (m, 6H), 1.30-1.09 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.14 (s, 6H). 13C NMR: δ 210.1, 177.3, 176.6, 60.1 (2×), 47.5, 42.57 (2×), 42.1, 40.4, 37.8, 30.0 (2×), 25.2 (2×), 24.7, 24.6, 24.2, 24.1, 15.7, 14.4, 14.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([N:11]=CN(C)C)=[N:7][C:6]=2[N:16]=1>C(O)C>[NH2:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:2]([Cl:1])=[N:16][C:6]=2[N:7]=1
Reactant: COc1ccc(-c2cc3cnc(N=CN(C)C)nc3nc2Cl)cc1
Solvent: CCO
Product: COc1ccc(-c2cc3cnc(N)nc3nc2Cl)cc1
Yield: 32.2 %

Procedure:
A mixture of 10 g of N'-(7-chloro-6-(4-methoxy-phenyl)-pyrido[2,3-d]pyrimidin-2-yl)-N,N-dimethyl-formamidine from Example 11 and 500 mL of 95% ethanol was refluxed for 3 hours. The solution was concentrated in vacuo and the precipitate collected by filtration. Crystallization from ethanol afforded 2.7 g of the title compound 2-amino-7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidine, mp 275°-280° C. dec.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.CO[CH2:15][CH2:16][C:17]12[CH2:24][CH2:23][C:20]([CH3:25])([CH2:21][CH2:22]1)[O:19][C:18]2=O.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[CH3:25][C:20]1[CH2:23][CH2:24][C:17]2([C:18](=[O:19])[N:8]([C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)[CH2:15][CH2:16]2)[CH2:22][CH:21]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COCCC12CCC(C)(CC1)OC2=O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1=CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(Trifluoromethoxy)-aniline (0.065 mL, [CAS Reg. No. 461-82-5]) was added to a solution of 4-(2-methoxy-ethyl)-1-methyl-2-oxa-bicyclo[2.2.2]octan-3-one (64 mg, obtained in example 59, step 1) in toluene (5 mL). The mixture was stirred for 10 minutes at r.t. Then, dimethylaluminiumchloride (1M in hexane, 0.65 mL) was added dropwise over a period of 5 minutes. The reaction mixture was stirred at reflux for 3 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give 8-methyl-2-(4-trifluoromethoxy-phenyl)-2-aza-spiro[4.5]dec-7-en-1-one as a light yellow solid as the main product (81 mg, 77%). MS (m/e)=326.4 [MH+]. From this reaction, a small amount of (5α,8α)-8-hydroxy-8-methyl-2-(4-trifluoromethoxy-phenyl)-2-aza-spiro[4.5]decan-1-one (see example 57) was also isolated (6 mg, 5%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(Cl)Cl>O.C1COCC1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Yield: 83 %

Procedure:
To a solution of NaOH (1.69 g, 42.2 mmol) in H2O (11 mL) was added a solution of triethylene glycol monomethyl ether (5.00 mL, 31.9 mmol) in THF (11 mL) under nitrogen, while the temperature was maintained below 5° C. by cooling with an ice-salt bath. At the same temperature, a solution of p-toluenesulfonyl chloride (6.08 g, 31.9 mmol) in THF (13 mL) was added dropwise over 1 h. The reaction mixture was poured into water and DCM was added. The layers were separated, and the aqueous layer was extracted with DCM (three times). The combined organic layers were washed with water (twice) and brine (twice), dried over anhydrous MgSO4, filtered off and evaporated to dryness to give 16 (8.43 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 4.16 (t, 2H), 3.50-3.70 (m, 10H), 3.32 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: COCCOC[N:7]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:8]1[CH3:30].CC(C)=O.Cl>C(Cl)Cl.O.C1COCC1>[CH3:30][C:8]1[NH:7][C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCCOCN1C(C)=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
The resolved mono-ester of formula 18 is then deprotected by acid hydrolysis using a dilute (about 1N to about 2N) mineral acid in a suitable water-miscible solvent (preferably acetone or THF) at a temperature between about 0° and about 15° C. for about 30 to about 120 minutes. For example, (R)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is dissolved in CH2Cl2, treated with 1N HCl at 0° C., and allowed to stand for one hour at room temperature. Then, water (100 mL) is added, and the resulting precipitate is filtered to yield (R)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (19). (Scheme VI, Step 5)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28][CH2:29][CH2:30]CCC.C(Br)C=C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH2:30][CH:29]=[CH2:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Reactant: CCCCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and was washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 156 mg (36%); 432 (M+H); 1H NMR: δ 7.90(1H, s, NH), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 5.99(1H, m), 5.13(2H, m), 4.71(2H, m), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: [CH2:1]([S:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C.O>[Br:11][C:8]1[S:7][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1
Reactant: CCCCSc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCSc1ccc(Br)s1
Reaction time: 0.5 h

Procedure:
A solution of compound 6 (5.18 g, 0.030 mol) and N-bromosuccinimide (5.34 g, 0.030 mol) in chloroform (80 ml) and glacial acetic acid (80 ml) was gently heated under reflux (with stirring) for 0.5 h (glc analysis revealed a complete reaction). The reaction mixture was diluted with water and washed with dichloromethane (2×100 ml); the combined organic extracts were washed successively with water (300 ml) and aqueous potassium hydroxide (5%, 300 ml) before being dried (MgSO4). The solvent was removed in vacuo and the residue was distilled to give a colourless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[O:21][CH3:22])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.CCOC(C)=O.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])=[CH:16][C:15]=1[O:21][CH3:22])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(O)ccc1[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A mixture of [(R)-2-hydroxy-1-(4-hydroxy-2-methoxy-phenyl)-ethyl]-carbamic acid benzyl ester (736.3 mg, 2.32 mmol), TBSCl (840.2 mg, 5.57 mmol) and imidazole (757.2 mg, 11.1 mmol) in DCM was stirred at rt for 24 h. The reaction was worked up with EtOAc/H2O. Flash column provided the titled compound (585.7 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:57][S:54]([CH:51]5[CH2:53][CH2:52]5)(=[O:56])=[O:55])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42), (80 mg, 0.147 mmol) and carbonyldiimidazol (48 mg, 0.295 mmol) in dry THF (25 mL) was stirred at reflux under nitrogen for 3 h. Then, the reaction mixture was cooled down to room temperature and cyclopropylsulfonamide (54 mg, 0.442 mmol) and DBU (52 mg, 0.34 mmol) were added. The resulting solution was stirred at 50° C. for 48 h. Then, the reaction mixture was partitioned between AcOEt ethyl acetate and water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05) to give the title product contaminated with cyclopropylsulfonamide. This solid was triturated 10 min in water and filtered, washed with water, dried under high vacuum, triturated again in diethylether and filtered to give 37 mg (39%) of the title product 43 as a white powder: m/z=647 (M+H)+; 1H-NMR (CDCl3): 10.40 (br s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.55 (s, 1H), 7.15 (s, 1H), 7.10 (dd, J=9.12 Hz, 2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 5.85 (br s, 1H), 5.65 (dd, J=18.2 Hz, 8.0 Hz, 1H), 5.15 (t, J=10.0 Hz, 1H), 4.8 (t, J=7.2 Hz, 1H), 4.10 (dd, J=11.3 Hz, 3.8 Hz, 1H), 3.9 (s, 3H), 3.60-3.70 (m, 1H), 3.6 (d, J=11.3 Hz, 1H), 3.10-3.20 (m, 1H), 2.90-3.00 (m, 1H), 2.85 (s, 3H), 2.4-2.6 (m, 3H), 1.90-2.20 (m, 3H), 1.25-1.60 (m, 7H), 0.90-1.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].S(=O)(=O)(O)O.[Br:21]Br.C(O)(=O)C.BrBr.CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[C:7]([Br:21])[N:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1ncc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was dissolved in water (300 ml). Sulfuric acid (4.60 ml, 86 mmol) was added followed by dropwise addition over 30 minutes of a solution of bromine (2.222 ml, 43.1 mmol) in acetic acid (29.6 ml, 517 mmol). The reaction mixture was stirred at RT for 18 hours. A further 100 ml of water was added, followed by a further 0.25 equivalents of the bromine/AcOH mixture (550 μL bromine in 7.4 ml AcOH) and the reaction mixture stirred at RT for an additional 90 minutes. The reaction mixture was diluted with 500 ml water and neutralised by addition of solid NaHCO3 (˜85 g). The suspension was extracted with DCM (3×300 ml) and the combined organic phases washed with sat.NaHCO3(aq) (250 ml), water (250 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo. The crude material was recrystallised from boiling MeOH (˜300 ml) to give the title product as a pale orange solid m/z 301.0 (95) [M+H]+ 1H-NMR: (400 MHz, DMSO-d6 δH 7.77 (1H, s, ArH), 7.17 (2H, s, NH2), 3.86 (3H, s, ArCO2CH3).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:10]1([CH:9]=[N:16][OH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11]1
Reactant: ON=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=CC1(Cl)C=CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-chlorosuccinimide (4.63 g, 34.7 mmol) was added to a solution of benzaldehyde oxime (3.5 g, 28.9 mmol) in DMF (30 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being pooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethylbenzene was obtained as a yellowish solid (4.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 11.64 g. of p-benzyloxybenzyl chloride and 50 ml. of hexamethylphosphoramide are heated in an oil bath at 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. of water, chilled and the solid mass diluted with additional water in order to filter. The solid is washed with water and recrystallized from ethanol to give off-white crystals, m.p. 144°-146° C. A sample is recrystallized from ethanol to give off-white crystals, m.p. 146°-147° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:16][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:17])[N:7]3[C:18]([CH3:21])=[CH:19][S:20][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3cccc(F)c3)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 43.8 %

Procedure:
A mixture of single enantiomer 7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.125 g, 0.412 mmol) made from above, 6-bromo-9H-purine (0.148 g, 0.742 mmol), and N,N-diisopropylethylamine (0.144 mL, 0.824 mmol) in ethanol (1.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.076 g, 44%). LCMS calculated for C20H17FN7OS (M+H)+: m/z=422.1. Found: 422.0. 1H NMR (DMSO-d6, 500 MHz) δ 8.05 (2H, s), 7.43 (1H, m), 7.24˜7.14 (5H, m), 6.99 (1H, s), 5.08 (1H, m), 2.59 (3H, s), 1.29 (3H, d, J=6.5 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −114 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[O:15][C:13](=O)[C:12]2=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+].Cl.[CH2:26]([NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13]([OH:15])=[C:31]([C:32]([O:34][CH3:35])=[O:33])[N:30]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16]2=[O:17])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)c2cc(OCc3ccccc3)ccc21
Reactant: COC(=O)CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
To a suspension of 4-benzyloxyphthalic anhydride (25.42 g, 100 mmol) in methanol (200 mL) was added 28% sodium methoxide methanol solution (21.22 g, 110 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (150 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (200 mL) and methyl 2-(isobutylamino)acetate (17.42 g, 120 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.00 g, 120 mmol) and 1-hydroxybenzotriazole (18.34 g, 120 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (50 mL) and a solution of 28% sodium methoxide methanol solution (38.59 g, 200 mmol) was added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (200 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give methyl 7-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (4.76 g, 12.1%) as an oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:43]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of 3β-hydroxy-5α-pregnan-20-one (285 mg, 318.5 g/m, 0.89 mmol), triphenylphosphine (258 mg, 262.3 g/m, 0.94 mmol), and benzoic acid (120 mg, 122.2 g/m, 0.98 mmol) were dissolved in 25 mL of tetrahydrofuran (freshly distilled). To this stirred reaction mixture at room temperature was added a solution of diisopropylazidodicarboxylate (DIAD) (0.194 mL, 1.027 g/ml, 202.2 g/m, 0.98 mmol) in 5 mL of tetrahydrofuran dropwise over a period of 5 minutes. The reaction was followed by thin layer chromatography (TLC) as the starting material was consumed. After two hours, the reaction mixture was concentrated under reduced pressure and filtered through a bed of silica gel (10 g) with a mixture of hexane/ethyl acetate (9:1). Fractions corresponding to the title compound were concentrated to give 349 mg of 3α-benzoyloxy-5α-pregnan-20-one (92% yield) as a white solid.