Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH:13](C)[CH2:12]2)=[N:3]1.CC1CNCCN1>>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[C:4]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[N:3]1
Reactant: CC1CN(c2nn(C)c(=O)n(C)c2=O)CCN1
Agent: CC1CNCCN1
Product: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Yield: 58 %

Procedure:
The synthesis of the intermediate 12c is achieved from 2-methyl-piperazine according to the operating procedure described for the synthesis of 12a (solid, yield: 58%).
Reaction SMILES: O=C1C2C(=CC=CC=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH:21]=2)[NH:16][CH:15]=1.[OH2:27].NN>C(O)C>[C:20]1([CH2:23][O:27][C:4]([NH:3][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH:21]=3)[NH:16][CH:15]=2)=[O:11])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: O
Reactant: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: NN
Solvent: CCO
Product: NC(=O)Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetamide (17.55 g) and hydrazine hydrate (12 ml) in ethanol (700 ml) was heated at reflux for 2 h. The resulting suspension was cooled to ambient temperature and all the solvent was evaporated in vacuo. The resulting yellow solid was dissolved in dilute sodium hydroxide (250 ml) and tetrahydrofuran (100 ml) and treated with benzylchloroformate (21 ml) at 5°. Stirring was continued for 1 h at ambient temperature, reaction mixture extracted with ethylacetate (4×200 ml), dried (MgSO4) and solvent removed to give crude product as an oil which on trituration with ethylacetate gave the title compound as a white solid (6.4 g) m.p. 124°-5°.
Reaction SMILES: CN1C([C:7]2[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)=C(C2C=CN=CC=2)N=N1.[N:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][N:39]=[C:38]2C2C=CC(O)=CC=2)=[CH:33][CH:32]=1.Cl.ClCC1C=CC2C(=CC=CC=2)N=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[N:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][N:39]=[C:38]2[C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:23][CH:24]=2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(-c2nccn2-c2ccncc2)cc1
Reactant: Cn1nnc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Product: c1ccc2nc(COc3ccc(-c4nccn4-c4ccncc4)cc3)ccc2c1
Yield: 84 %

Procedure:
According to the procedure for preparation of 2-((4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline, 4-(1-(pyridin-4-yl)-1H-imidazol-2-yl)phenol (90 mg), 2-(chloromethyl)quinoline hydrochloride (81 mg) and cesium carbonate (495 mg) gave 120 mg as an off-white solid (84%). 1H NMR (CDCl3, 400 mHz) δ 8.59 (m, 2H), 8.16 (d, 1H, J =8.3 Hz), 8.04 (d, 1H, J=8.3 Hz), 7.79 (d, 1H, J=7.9 Hz), 7.70 (ddd, 1H), 7.60 (d, 1H, J=8.3 Hz), 7.52 (ddd, 1H), 7.28 (m, 2H), 7.22 (d, 1H, J=1 Hz), 7.15 (d, 1H, J=1 Hz), 7.11 (m, 2H), 6.94 (m, 2H), 5.34 (s, 2H). HPLC-MS (system 1) 4.53 min, m/e 379 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].[PH2]([O-])=O.[Na+].[OH-].[K+].C([N-]CCCC)CCC>>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)C1CCCO1
Reactant: CCCCNCCCC
Agent: CCCC[N-]CCCC
Agent: O=[PH2][O-]
Agent: [K+]
Product: CCCCN(CCCC)C(=O)C1CCCO1
Temperature: 200 °C

Procedure:
232 g (2 mols) of 2-tetrahydrofuroic acid, 387 g (3 mols) of dibutyl amine and 1,5 g of sodium hypophosphite, were introduced into a stirred reactor at room temperature. Reaction mixture was gradually heated up to 200° C., separating the reaction water and returning the excess of dibutyl amine into the reactor. Reaction was controlled by its acid value. Once the acid value was lower than 10 mg KOH/g, excess of dibutyl amide was distilled at 60-100° C. under vacuum.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][OH:30]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: COCCCO
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: COCCCOc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 9 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro cyclohexyl methyl)-amide and 3-methoxy-propan-1-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.79-8.82 (m, 1H), 7.95 (d, J=9.11 Hz, 1H), 7.79 (d, J=9.01 Hz, 1H), 7.70 (d, J=9.01 Hz, 1H), 7.12 (d, J=9.12 Hz, 1H), 4.45 (t, J=13.2 Hz, 2H), 3.49 (t, J=12.61 Hz, 2H), 3.25 (s, 5H), 1.97-2.04 (m, 4H), 1.80-1.86 (m, 3H), 1.73-1.76 (m, 2H), 1.23-1.32 (m, 2H). m/z: 427.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[C:13]([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=O)(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:20][CH2:19][N:18]=[C:17]1[NH:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCNC1=O
Reactant: CC(C)c1cc(N)n(C(C)C)n1
Product: CC(=O)N1CCN=C1Nc1cc(C(C)C)nn1C(C)C

Procedure:
5-Amino-1,3-di-isopropyl pyrazole (13.5 g.) and 1-acetyl-2-imidazolidinone (12.2 g.) were reacted as described in Example I to give 13.01 g. of product, mp 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][N:18]([CH3:19])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Product: CN(C)CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Yield: 87 %

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and dimethyl amine using General Procedure G1, followed by General Procedure E in 87% yield. LCMS Rt=8.69 min, m/z=272 (M+1). 1H NMR (CDCl3, δ): 7.40 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 2.43 (s, 2H), 20.1 (s, 6H), 2.0-1.6 (m, 8H). 13C NMR (CDCl3, δ, mult): 149.2(0), 129.5(0), 129.2(1), 126.7(1), 131.6(1), 69.3(2), 52.1(0), 48.0(3), 36.0(2), 23.2(2),
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O>C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=3[C:7](=[O:9])[C:14]=2[CH:15]=1
Reactant: O=C(O)c1cc(Br)ccc1COc1ccc(Br)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2cc(Br)ccc2COc2ccc(Br)cc21
Temperature: 0 °C
Yield: 47 %

Procedure:
A solution of 5-bromo-2-(4-bromophenoxymethyl)benzoic acid (100 g, 0.26 mole), and trifluoroacetic anhydride (160 mL) in one liter of methylene chloride containing 20 drops of boron trifluoride-ether complex was refluxed for three hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/ethyl acetate (9:1) gave the ketone (45 g) mp 193°-194° C. pmr (DMSO-d6) δ: 8.12 (d, J=2.7 Hz, 1H, H10), 7.27-7.91 (m, 4H, aromatic H), 7.10 (d, J=8.8 Hz, 1H, H4), 5.32 (s, 2H, ArCH2O).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:26]([O:28]C)=[O:27])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:14])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:26]([OH:28])=[O:27])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccc(O)cc2)C(=O)O)cc1
Yield: 55.9 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 37 (2.5 g), 1 mol/L of an aqueous sodium hydroxide solution (19 mL), and methanol (190 mL), to give the captioned compound (1.2 g, 57%) as an amorphous solid product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4](Cl)[N:3]=1.[NH3:22].CO>>[N:18]([C@H:13]1[CH2:12][C@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[NH2:22])[O:15][C@@H:14]1[CH2:16][OH:17])=[N+:19]=[N-:20]
Reactant: N
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Cl)nc(N)nc32)O[C@@H]1CO
Solvent: CO
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Temperature: 80 °C
Yield: 58 %

Procedure:
A mixture of compound 77 (190 mg, 0.61 mmol) and NH3/CH3OH (30 mL) was heated to 80° C. at seal bomb for 18 h, then cooled to room temperature. The reaction mixture was evaporated and purified by flash column chromatography with dichloromethane:ethyl acetate:methanol=7:7:1 to obtain the white solid 100 mg 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:5]([NH:8]C=O)([CH3:7])[CH3:6].Cl.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:5]([NH2:8])([CH3:6])[CH3:7]
Reactant: CC(C)(NC=O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(N)c1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
A mixture of 1.16 g (5 mmol) of N-(3,5-dichloro,α,α-dimethylbenzyl)formamide and 8 ml of 2N hydrochloric acid was refluxed for 30 minute. After cooling, the reaction solution was alkalified with a sodium hydroxide aqueous solution and extracted with diethyl ether. The ether solution was washed with water, dried and then concentrated to obtain 1.0 g (yield: 98.0%) of the desired compound.
Reaction SMILES: C(O)=O.[CH3:4][N:5]([CH3:36])[C:6](=[O:35])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:17])=[C:10]([F:34])[CH:9]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:34][C:10]1[CH:9]=[C:8]([O:7][C:6](=[O:35])[N:5]([CH3:4])[CH3:36])[CH:13]=[CH:12][C:11]=1[CH2:14][NH:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][CH2:65][C@H:63]([OH:64])[CH2:62][O:61][C:58]3[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=3)=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C(=O)Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c(F)c1
Solvent: O=CO
Product: CN(C)C(=O)Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1

Procedure:
4-{[({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)amino]methyl}-3-fluorophenyl dimethylcarbamate formate (0.225 g, 0.6 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure give the title compound (0.125 g, 0.1 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:50])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26](COCC[Si](C)(C)C)[C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:50])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[NH:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:27]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCN(CCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C)C(=O)Nc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCN(CCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Yield: 53.2 %

Procedure:
Part D. To a solution of N'-(2,4-difluorophenyl)-N-[6-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexyl]-N-heptylurea (0.60 g, 0.000853 mol) in dry tetrahydrofuran (10 mL) under a nitrogen atmosphere, tetrabutylammonium fluoride (1M in tetrahydrofuran, 3.41 mL) was added and the reaction mixture was heated to reflux 7 hours. The reaction mixture was cooled, poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel (75 mL) eluting hexane:ethyl acetate (60:40 v:v) to give the title compound as a colorless glass (0.26 g, 0.000454 mol). 1H NMR (CDCl3) δ9.5-9.0(bs,1H), 7.87(m,1H), 7.5-7.2(m,10H), 6.83-6.7(m,2H), 6.4(d,1H), 3.28(m,4H), 2.67(t,2H), 1.75-1.26(m,18H), 0.88(t,3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[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]([Cl:22])[Cl:21].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17](=[O:19])[CH:20]([Cl:22])[Cl:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCCl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Cl)Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Methyl ester (1.4 g) of N-tert-butoxycarbonyl-L-phenylalanine (1.4 g) was dissolved in dehydrated tetrahydrofuran (20 ml), and the obtained solution was cooled to −78° C. Methylene chloride (0.64 ml) and then 2 M solution (7.5 ml) of lithium diisopropylamide in heptane, tetrahydrofuran and ethylbenzene were added thereto, and they were stirred for 1 hour. A saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture to terminate the reaction. The temperature was elevated to room temperature. After the extraction with ethyl acetate and water, the obtained solution in ethyl acetate was analyzed by HPLC to find that the intended (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.86 g) was obtained in a yield of 52%. The obtained solution in ethyl acetate was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue to form a slurry. The crystals thus formed were separated from the slurry and dried to obtain the intended (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.65 g) in a yield of 36%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution containing 4,6-dimethyl-2-methylsulfonylpyrimidine (10.0 g, 53.8 mmol), ethyl glycolate (5.60 g, 53.8 mmol), and 30 mL of N,N-dimethylformamide was prepared and to this was added with stirring potassium carbonate (8.0 g, 60 mmol). The mixture was allowed to stir at ambient temperature overnight. It was then poured into water and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were extracted with water. The aqueous extract was saturated with sodium chloride and extracted twice more with ethyl acetate. All of the ethyl acetate layers were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 8.20 g (72.6 percent of theory) of the title compound as a yellow oil. This oil was filtration chromatographed on silica gel, eluting with a 30:70 mixture of ethyl acetate and hexane. The product containing eluate was concentrated by evaporation under reduced pressure to obtain 7.9 g (70 percent of theory) of the title compound as a colorless oil which solidified on standing to a white solid melting at 57°-59° C.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:21]=2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: C=CCOC(=O)c1c(C)cccc1N
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1c(C)cccc1NC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCC=C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (2.3 g, 8.6 mM), allyl 2-amino-6-methylbenzoate (1.5 g, 7.8 mM), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 g, 10 mM) were dissolved in toluene (30 ml) and stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with a 2M aqueous solution of HCl (3 by 30 ml), water, a saturated aqueous solution of NaHCO3, and brine. Drying over MgSO4 and evaporation of the solvent gave (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-allyloxycarbonyl-3-methylphenylcarbamoyl)pyrrolidine as a gum (3.4 g, 97%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:29].[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)#[CH:32].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:22]2[CH:27]=[CH:26][C:25]([C:32]#[C:31][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:24][CH:23]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(C#Cc3ccccn3)cc2)cc1C

Procedure:
A solution of (Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (283 mg, 0.55 mmol), 2-Ethynyl-pyridine (0.167 ml, 1.65 mmol), bis(triphenylphosphine) palladium(II) chloride (0.015 g, 0.022 mmol), copper(I) iodide (0.31 mg, 0.002 mmol) in dry triethylamine (4 ml) were heated to 120° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding {2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynylphenyl)-allyloxy]-phenoxy}-acetic acid methyl ester as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[OH:15][CH2:14][CH:12]1[CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=[CH:11]1
Reactant: CC(C)(C)OC(=O)NC1C=CC(C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C=CC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
4-t-Butoxycarbonylaminocyclopent-2-enecarboxylic acid (1 g, 4.4 mmol) was dissolved in THF (10 mL) and borane-THF (1.5 mL, 1M solution) was added drop-wise at 0° C. and stirred overnight at rt. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ethyl acetate (2×50 mL). The ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and evaporated to yield N-[4-(hydroxy-methyl)cyclopent-2-enyl](t-butoxy)carboxamide (655 mg, 69%). ESMS: 214 (M+1)+, 236 (M+23)+, 248 (M+35)−, 272 (M+59)−. 1H NMR (CDCl3): δ 1.40 (s, 9H), 2.16 (s, 1H), 2.44-2.52 (m, 2H), 2.82-2.83 (m, 1H), 3.54-3.66 (m, 2H), 5.74-5.81 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][N:17]4C3CCCCO3)[CH3:11])[N:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.Cl>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][NH:17]4)[CH3:11])[N:7]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:6]=2[CH:34]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Alternatively, [(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (30 g, 65.6 mmol) was dissolved in EtOAc (200 mL) and HCl (1 M in MeOH, 210 mL) was added dropwise and the resulting solution was stirred for 2 h. The solvents were removed in vacuo and the resulting solid was recrystallised from hot EtOAc/EtOH to give 123 as a white crystalline solid (11 g, 45%). Further product crystallised from the mother liquors. 1H NMR (MeOD-d4, 400 MHz): δ 8.60 (1H, s), 8.53 (1H, s), 7.8 (1H, dd, J 9.8, 4.2 Hz), 7.67 (5H, br s), 7.42 (1H, td, J 9.2, 2.3 Hz), 7.14 (1H, dd, J 7.1, 2.4 Hz), 5.67 (1H, m), 1.87 (3H, d, J=6.9 Hz)
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:8][OH:9])[S:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH2:15][O:16][CH2:17][C:18]2SC=C[CH:19]=2)SC=CC=1>CCOCC>[C:3]1([CH2:8][O:9][CH2:10][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[S:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccs1
Reactant: c1csc(COCc2cccs2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: c1coc(COCc2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl ether. To a suspension of 1.32 g. (0.01 mole) of cloromethylthiophene [obtained by the method of F. F. BLICKE, J.A.C.S. 64, 477 (1942)] and 1.2 g. (0.02 mole) of powdered potassium hydroxide in 10 ml. of ether there is added a solution of 3.5 g. (0.03 mole) of thenyl alcohol in 10 ml. of ether. The reaction mixture is stirred for 1 hour at room temperature, then refluxed for 30 minutes and finally allowed to stand over night. After filtration the ethereal solution is concentrated and the residue fractionally distilled. There is obtained 0.22 g. (10%) of dithenyl ether having a b.p. of 99°C./0.01 mm. Hg. and a m.p. of 36.5°. 1c. Furfuryl thenyl ether is obtained by the same method as used for preparing compound (1) b., but using furfuryl alcohol instead of thenyl alcohol. The product thus obtained had a b.p. of 50°C./0.01 mm. Hg.