Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:15]=[CH:16][CH:17]=[C:4]12)[CH3:2].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[CH3:36]>C(Cl)Cl>[CH2:1]([CH:3]1[N:12]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[C:27]([CH3:36])[CH:28]=2)(=[O:34])=[O:33])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:15]=[CH:16][CH:17]=[C:4]12)[CH3:2]
Reactant: CCC1Nc2cc(F)c(F)cc2-n2cccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
1.35 g (5.0 mmol) of the product from Example 3 was dissolved in 40 ml of methylene chloride and 1 ml of pyridine added. To this solution was added 1.20 g (5.4 mmol) of 4-methoxy-3-methyl benzenesulfonyl chloride. The solution was stirred at room temperature for 6 hours, after which it was concentrated, then diluted with 5 ml of 2N HCl. The residue was extracted 2 times with ethyl acetate, dried (MgSO4) and concentrated. The crude solid so obtained was chromatographed on silica gel, eluting with 20% ethyl acetate:hexane to afford a light yellow solid, which can be recrystallized from ethyl acetate:hexane to yield 1.52 g (72%) of product.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:4](=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]3[C:44]4[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=4)[CH2:38][N:37]([CH3:47])[CH2:36]3)[CH:30]=2)(=[O:28])=[O:27])=[O:12])(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C(O)c1ccccc1C(=O)O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccccc3C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 59.8 %

Procedure:
Compound 230 was prepared by following the procedure outlined in Example 215 using phthalic acid (8.0 mg, 0.0484 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 75 mg, 0.0968 mmol). Purification by preparative HPLC gave the title compound (35.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (d, 2H), 7.76 (s, 2H), 7.63 (t, 2H), 7.50 (m, 8H), 6.79 (s, 2H), 4.83-4.73 (m, 4H), 4.65 (d, 2H), 3.85 (q, 2H), 3.62-3.39 (m, 36H), 3.10 (s, 6H), 3.02 (t, 4H). MS (m/z): 1223.00 [M+H]+.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14].[OH-].[Na+].N1C(C)=CC=CC=1C.O([Si](C(C)C)(C(C)C)C(C)C)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.C1C=CC=CC=1.CCOCC>[CH:4]([O:5][C:6]1[CH:7]=[C:8]([CH2:16][O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:25]([CH3:26])[CH3:27])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:14])[F:15])=[CH2:3]
Reactant: CC(C)[Si](OCc1ccc(OC(F)F)c(OCCCl)c1)(C(C)C)C(C)C
Agent: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the chloride, 3-(2-Chloro)ethoxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene, from Step 2 (124 g, 303 mmol), 10N NaOH (300 mL, 3.03 mol) and Bu4NHSO4 (102 g, 303 mmol) in benzene (1.3 L) was heated at 65° C. for 4.5 h. The mixture was cooled to room temperature and was partitioned with 25% aq. NH4OAc (5 mL). The aqueous phase was extracted with ether (2×) and the combined organics were washed with brine, dried (Na2SO4) and concentrated. The residual oil was dissolved in dichloromethane (1 L) and 2,6-lutidine (53 mL, 454 mmol) and cooled in an ice bath. Triisopropylsilyl triflate (98 mL, 363 mmol) was slowly added and after addition was complete, the mixture was stirred at room temperature for 3 h. The mixture was cooled to 0° C. and sat. aq. NaHCO3 (50 mL) was added. Ether (1.5 L) and 25% aq. NH4OAc (500 mL) were added and the aqueous layer was extracted with ether (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 98:2 to 95:5) provided 3-Ethenyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene (67 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:13]#[N:14])([C:8]([O:10]CC)=[O:9])[CH2:3]1.[OH-].[K+]>>[C:13]([C:4]1([C:8]([OH:10])=[O:9])[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)#[N:14]
Reactant: CCOC(=O)C1(C#N)CCCC(C)C1
Agent: [K+]
Agent: [OH-]
Product: CC1CCCC(C#N)(C(=O)O)C1

Procedure:
This ester is hydrolyzed by heating with ethanolic potassium hydroxide solution. Neutralization, extraction with methyl tert.-butyl ether and distillative removal of the solvent gives 1-cyano-3-methylcyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:29]=[O:30])[CH:8]=2)[S:3]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)cc1
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To a cold (−78° C.) solution of 2,2-dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound N, 280 mg, 0.81 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M solution, 0.66 mL). The mixture was gradually warmed to −10° C. over 25 min. and recooled to −78° C. To this solution was added DMF (80 mg, 1.1 mmol) and stirred at ambient temperature for 5 hours. The reaction was quenched by adding water (10 mL), ethyl acetate (100 mL), and the organic layer was washed with brine (10 mL), dried and the solvent removed by distillation. The crude material was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:33]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:33][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:30])([F:31])[F:32])[C:23]=3[F:22])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1cnc(Nc2cccc(C(F)(F)F)c2F)nc1C(F)(F)F
Yield: 15.2 %

Procedure:
In a manner similar to Example 242, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) and 2-fluoro-3-trifluoromethylphenylamine (Aldrich) (156 mg) were reacted to give the title compound (11 mg)
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([S:18](Cl)(=[O:20])=[O:19])[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[CH:17]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([S:18]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:19])=[O:20])[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc2nccnc12
Reactant: NC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NC1CCCC1)c1cc(Cl)cc2nccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclopentyl amine (0.134 mg, 1.6 mmol) in pyridine (5 ml) was added a solution of 7-chloroquinoxaline-5-sulfonyl chloride (0.26 g, 0.748 mmol, crude) in DCM (5 mL) at 0° C. The reaction was stirred at room temperature for 15 minutes before being partitioned between brine and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf=0.38 in 1:1 hexanes/ethyl acetate) afforded 7-chloro-N-cyclopentylquinoxaline-5-sulfonamide as an off-white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:30][C:31]([F:39])(S(F)(=O)=O)C(O)=O>C(#N)C>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:14][O:15][CH:31]([F:39])[F:30])[C:10]([O:12][CH3:13])=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)C(CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Yield: 4.8 %

Procedure:
To an acetonitrile solution of methyl 2-(dibenzylamino)-3-hydroxypropanoate (23 g, 76.8 mmol) and sodium sulfate (3.9 g, 27.4 mmol) at 40° C., difluoro(fluorosulfonyl)acetic acid (25 g, 140 mmol) was added dropwise for 1.5 hrs. The reaction mixture was concentrated to dryness and the residue was mixed with silica gel in ethyl acetate, then again concentrated to dryness. The product was purified by column chromatography, eluting with 3-4% ethyl acetate in hexanes, to give methyl 2-dibenzylamino-3-difluoromethoxy-propionate (1.3 g, 4.8%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.20-7.40 (m, 10H), 6.18 (bt, 1H), 4.05-4.24 (m, 2H), 3.90 (d, 2H), 3.83 (s, 3H) and 3.64-3.71 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1ccc(C2CNCCN2)o1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(C)o4)C3)cc21
Yield: 27.6 %

Procedure:
A mixture of 4.98 g of 2-(5-methyl-2-furanyl)piperazine and 2.69 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was refluxed for 48 hours and then evaporated. The residue was chromatographed on silica gel eluting with chloroform:methanol:water (9.5:0.5:0.02), giving 1.1 g of the desired product, mp 186°-188° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)[CH2:19][CH2:18]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 120 °C

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (300 mg, 1.368 mmol), N-cyclopropyl-4-(piperazin-1-yl)benzamide (336 mg, 1.368 mmol), (cyanomethyl)trimethylphosphonium iodide (499 mg, 2.053 mmol) and N,N-diisopropylethylamine (1195 μl, 6.84 mmol) were suspended in propionitrile (Volume: 4109 μl) and heated in a closed vial at 120° C. for 2 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (1:1, 15 mL), and then from MeOH:EtOH:water (1:1:1, 10 mL), washed with water (3 mL) and dried in vacuum to give a light green solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:20])#[N:2].[CH2:21]([C:23]1([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH2:21]([C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][N:25]([C:15](=[O:17])[CH2:14][CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[C:4]([F:20])[CH:5]=3)[CH:9]=[N:10][CH:11]=2)[CH2:24]1)[CH3:22]
Reactant: CCC1(c2cccc(O)c2)CCCCNC1
Reactant: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC1(c2cccc(O)c2)CCCCN(C(=O)CCc2cncn2Cc2ccc(C#N)c(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[3-(4-Cyano-3-fluoro-benzyl)-3H-imidazol-4-yl]-propionic acid, as described above in Step E, (0.56 g, 0.78 mmol) and 3-(3-ethyl-azepan-3-yl)-phenol, as described above in Step J, (0.182 g, 0.78 mmol), HOBT (0.126 g, 0.936 mmol), EDC (0.179 g, 0.936 mmol) and N-methylmorpholine (0.257 mL, 2.34 mmol) were dissolved in DMF (15 mL) and stirred at ambient temperature for 18 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with H2O, brine, dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[O:22]1[CH2:27][CH2:26][NH:25][C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2>CN(C)C(=O)C.O>[O:22]1[CH2:27][CH2:26][N:25]([C:9]([C:5]2[C:6]([OH:8])=[N:7][C:2]([OH:1])=[N:3][CH:4]=2)=[O:11])[C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2
Reactant: c1cc2c(cn1)NCCO2
Reactant: O=C(O)c1cnc(O)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(c1cnc(O)nc1O)N1CCOc2ccncc21
Reaction time: 0.33 h
Yield: 21.4 %

Procedure:
2,4-dihydroxy-pyrimidin-5-carboxylic acid (125 mg, 0.80 mmol) was dissolved in N,N-dimethyl acetamide (3 ml) and then cooled to −150. Thionyl chloride (0.066 ml, 0.90 mmol) was added thereto at −15□ and the reaction mixture was stirred at −5□ for 20 minutes. The reaction mixture was cooled to −15□, and potassium carbonate (138 mg, 1.0 mmol) and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (109 mg, 0.80 mmol) were added thereto dropwise. The reaction mixture was stirred at −5□ for 30 minutes, and then stirred at room temperature for 3 hours. After the completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound 59 as white solid (47 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([O:25][CH2:26][CH2:27]I)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]([O:25][CH2:26][CH2:27][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCCI)c1ccccc1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCCn1ccc2ncnc(Cl)c21)c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (141 mg) in N,N-dimethylformamide (2.5 mL) was added cesium carbonate (358 mg) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 2-iodoethyl benzoate (298 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (50 mL), and extracted with ethyl acetate (50 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5→60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (205 mg) as a colorless transparent oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:28][NH:29][CH3:30].C1COCC1>>[CH3:28][N:29]([CH2:16][CH:14]1[CH2:13][CH:12]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:15]1)[CH3:30]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](n3cc(I)c4c(N)ncnc43)C2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CC(n2cc(I)c3c(N)ncnc32)C1

Procedure:
A mixture of cis-toluene-4-sulfonic acid 3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutylmethyl ester (1.50 g, 3.01 mmol) and a 2M solution of dimethylamine in THF (30 mL, 60 mmol) was heated to 55° C. for 23 h in a glass pressure tube. The solvent was evaporated, water was added, the mixture was extracted with CH2Cl2 (4×40 mL), and the extracts were washed with brine and dried over MgSO4. The crude material was chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-8)→5% MeOH in CH2Cl2 (9-24)→10% MeOH in CH2Cl2 (25-35)→10% MeOH in CH2Cl2 with 0.07M NH3 (36-48)], fractions containing product were combined and dried in vacuo. One obtained the title compound as brown solid. 1H NMR (CDCl3, 400 MHz): δ=2.01-2.11 (mc, 2H), 2.26 (s, 6H), 2.30-2.43 (mc, 1H), 2.46 (d, J=6.8 Hz, 2H), 2.69-2.77 (mc, 2H), 5.05-5.15 (mc, 1H), 5.59 (brs, 2H), 7.20 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 372.1 (20) [MH+]. HPLC: tR=1.3 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:19]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:20][NH:21][CH3:22]>O>[CH3:20][N:21]([CH3:22])[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:19]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(-c2cn3cccnc3n2)cc1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(-c2cn3cccnc3n2)cc1
Temperature: 50 °C

Procedure:
2.9 g (0.01 mol) of 2-(4-Chlorosulphonyl-phenyl)-imidazo[1,2-a]pyrimidine are suspended in 60 ml of a 40% solution of dimethylamine in water. The mixture is heated to 50° C. for 30 minutes, diluted with 50 ml of water, extracted with ethyl acetate, then the ethyl acetate extract is dried and evaporated to dryness. The residue is recrystallised from dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[C@@H:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1.[C:21]1([C:27](=O)[CH2:28][N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:19]#[N:20])[C@@H:10]([NH:12][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(Cn1cccn1)c1ccccc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@H](NC(Cn1cccn1)c1ccccc1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1

Procedure:
To a solution of 80 mg (0.28 mmol) of 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine in 1.5 mL of toluene, 60 mg of 1-phenyl-2(1H-pyrazol-1-yl)ethanone and 5 mg of TsOH were added. Powdered 4A molecular sieves (˜300 mg) were added to the reaction and it was heated to reflux for 5 hr. The mixture was allowed to cool overnight, filtered and the solid washed with EtOAc. The filtrate was concentrated and the residue was dissolved in 1.5 mL of THF, 0.1 mL of acetic acid. This solution was treated with 20 mg of NaCNBH3 for 1.5 hr. The reaction was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated. The residue was purified on a prep TLC plate using 50% EtOAC-hexane as eluant to isolate of the higher Rf isomer, 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-phenyl-2-(1H-pyrazol-1-yl)ethyl)amino)propyl)benzonitrile (Diastereomer A) LC-MS: m/e=455 (M+1), 457 (M+3) (3.16 min). and the lower Rf isomer, 3-(1(S)-(4-chlorobenzyl)-2(S)-(1-phenyl-2-(1H-pyrazol-1-yl)ethyl)amino)propyl)benzonitrile (Diastereomer B) LC-MS: m/e=455 (M+1), 457 (M+3) (3.12 min).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1>C1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of aluminum chloride (1.27 g, 9.52 mmol) in 30 ml dry benzene under nitrogen was added at room temperature 4-chlorophenylacetyl chloride 0.80 g, 9.52 mmol) over a period of 30 minutes as a solution in 10 ml benzene. The resulting clear, pale yellow solution was refluxed for six hours. After cooling to room temperature, the resulting grey-brown solution was poured into 100 ml ice water. The layers were separated and the aqueous portion extracted with benzene (1×20 ml). The combined organic portions were washed with water (2×30 ml), 10% NaOH (1×30 ml), water (1×30 ml), and brine (1×30 ml), and dried over magnesium sulfate. Filtration through Celite afforded, after concentration in vacuo, 2.18 g of the ketone as a white crystalline solid (99% crude yield): Rf 0.46 (benzene); 1H NMR (CDCl3) 8.03 (d, J=7.2 Hz, 2H), 7.63-7.21 (m, 7H), 4.29 (s, 2H). A portion (ca. 1 g) of the ketone was recrystallized from 75 mi boiling pet. ether/ethanol (5:1) to give a fluffy white crystalline solid: m.p. 132.5°-134.0° C. (lit. m.p. 135°-136° C.; Loeshorn, C. H. et al., J. Org. Chem. 48:4409 (1983)).