Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][C:20](O)=[O:21])=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][N:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[CH2:19][CH2:18][C:17]2[C:13]([CH3:12])=[N:14][O:15][C:16]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CCc2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.47 g), 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.50 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.75 g, yield 79%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 140–141° C.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[N:17][CH:18]=1>ClCCl.C(N(C(C)C)CC)(C)C>[C:4]1([CH2:3][CH2:2][C:1]([NH:12][C:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
Hydrocinnamoyl chloride (0.037 mL, 0.25 mmol) in dichloromethane was added to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.070 g, 0.20 mmol) in dichloromethane (2 mL) and diisopropylethylamine (0.087 mL) at 0° C. The mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the title compound was obtained in 7.6% yield (7.3 mg) after column purification. 1H NMR (300 MHz, CDCl3) δ 7.99, 7.80, 7.71, 7.56, 7.27, 6.91, 6.61, 3.91, 3.57, 3.43, 3.27, 3.04, 2.64. MS (ES+) m/z 483.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([OH:24])[C@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15]>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH:24][CH2:13][C:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])=[O:15]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
oxidizing separately said D-sorbitol and D-mannitol to provide L-sorbose and D-fructose, respectively;
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2(C(O)=O)[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH2:15])[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CN1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(N)(c2ccc(F)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
TEA (1.3 mL) and diphenylphosphorylazide (0.98 mL) were added to a suspension of 4-(4-fluorophenyl)-1-methyl-4-piperidinecarboxylic acid hydrochloride (500 mg) in dry toluene (40 mL) under nitrogen atmosphere. The reaction mixture was heated at 90° C. and stirred overnight. Then it was cooled to rt and washed with an aqueous std K2CO3 solution. The aqueous layer was separated and the organic phase was dried and concentrated under vacuum to give a white solid. This material was suspended in HCl 5M (10 mL) and the reaction mixture was heated to reflux and stirred overnight. Then it was cooled to 0° C. and treated with aqueous 4M NaOH solution until pH=9. The aqueous layer was extracted with AcOEt, the combined organic extracts were washed with water and brine, dried and concentrated under vacuum to a residue which was purified by silica cartridge (from DCM to DCM/MeOH/TEA 90:5:5) to give the title compound (70 mg) as a white foam.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[CH:8][CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20](O)(=[O:22])[CH3:21]>>[CH3:21][C:20]([C:8]1[C:7]([OH:13])=[C:6]2[C:11](=[C:10]([OH:12])[CH:9]=1)[C:2]1([Cl:1])[C:14]([Cl:15])([Cl:16])[C:5]2([Cl:17])[C:4]([Cl:18])=[C:3]1[Cl:19])=[O:22]
Reactant: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: CC(=O)O
Product: CC(=O)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 40 °C

Procedure:
76 g. of 1,2,3,4,9,9-hexachloro-1,4-dihydro-1,4-methanonaphthalene-5,8-diol, prepared according to Example 2, were suspended in 100 ml. of acetic acid and then 20 ml. of boron trifluoride-diethyl ether complex were added. This mixture was heated at 100°-105° C for 5 hours. After being cooled to 40° C, the mixture was poured into ice water. After repeated recrystallization from benzene white crystals were obtained, m.p. 135°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:16]3[NH:17][CH:18]=[CH:19][N:20]=3)[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].[CH3:23]COC(C)=O>C(OCC)(OCC)OCC.[Cl-].[Na+].O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:23]=[CH:18][N:17]=[C:16]3[NH:20][CH3:19])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-n2cnc(CNc3ncc[nH]3)c2)cc1Cl
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CNc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Product: Cl

Procedure:
A suspension of 1-[[1-(3,4-dichloro-phenyl)-1H-imidazol-4-ylmethyl]-1H-imidazol-2-ylamine (0.7 g, 2.3 mmol) in triethyl orthoformate (10 ml) was stirred under reflux for 2 h. The reaction mixture was evaporated to dryness, dissolved in ethanol (10 ml) and cooled in an ice bath. Sodium borohydride (0.091 g, 2.4 mmol) was added and the mixture was allowed to slowly reach 20° C. After 18 h AcOEt and brine was added and the organic phase was separated, dried (Na2SO4) and concentrated. After chromatography [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] the free base of the title compound was obtained. It was crystallized as the off-white hydrochloride salt (0.25 g, 16%). Mp. >250° C. (MeOH/Et2O), MS: m/e=322 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15](OC3CCCC(=O)C=3)=[O:16])=[CH:11][N:10]=[C:9]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].[OH2:34].C([O:38][CH2:39][CH3:40])(=O)C>C(#N)C>[F:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]([C:6]3[C:7](=[O:34])[CH2:2][CH2:3][CH2:40][C:39]=3[OH:38])=[O:16])=[CH:11][N:10]=[C:9]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)OC2=CC(=O)CCC2)c1=O
Reactant: CCOC(C)=O
Reactant: O
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)C2=C(O)CCCC2=O)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-oxo-1-cyclohexen-1-yl 1-(3-fluoro-2-methylphenyl)-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxylate (i.e. the product from Example 5, Step C) (42 g, 100.4 mmol) in acetonitrile (200 mL) was added cesium fluoride (30.5 g, 200.8 mmol). The reaction mixture was stirred for 24 h at room temperature. Water and ethyl acetate was added to the reaction mixture and the water layer was extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was washed several times with ether and filtered, followed by the addition 60 mL of ethyl acetate and let stir for 2 h. The resulting solid was then washed again with ether and dried under reduced pressure to afford the title product, a compound of the present invention, as a yellow solid (26 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[Cl:16])=[C:4]([CH2:17][O:18][CH3:19])[N:3]=1.[Cl:20]C1C=C(Cl)C=CC=1CC#N.C(OCC(OCC)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:19]([O:18][CH2:17][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:20])=[CH:11][C:10]=1[Cl:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)COCc1ccccc1
Reactant: COCc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(COCc2ccccc2)n1

Procedure:
This compound was prepared in a manner analogous to the compound of Example 16 from 2,4-dichlorophenylacetonitrile and ethyl benzyloxyacetate, 3.77 gms, mp. 171°-172° C.
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].O.C(C=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:24]([O:26][CH:27]=[CH:28][CH:29]=[CH:30][CH3:31])[CH3:25].O1C=CC=CC1>>[CH3:31][CH:30]1[CH:29]=[CH:28][CH:27]([O:26][CH2:24][CH3:25])[O:2][CH:1]1[CH:3]=[O:4]
Reactant: CC=CC=COCC
Reactant: O=CC=O
Agent: C1=CCOC=C1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CCOC1C=CC(C)C(C=O)O1

Procedure:
Monomeric glyoxal was generated by heating a mixture of 8.0 g. of glyoxal hydrate (0.117 mol. of monomer) and 48.0 g. of phosphorus pentoxide over a gentle flame over 35 minutes. The liberated monomer was bubbled (argon stream) into 4.8 g. (0.04 mol) of 1-ethoxy-1,3-pentadiene (purity 92.3%) at 120°. After all the monomer had been generated, the solution was heated at 120° for an additional 45 minutes. Distillation afforded 1.32 g. of the pyran (b0.07 =56°, purity 91%) and 1.86 g. of recovered diene (yield based on diene-32%, based on glyoxal=6.6%).
Reaction SMILES: [C:1]([C:4]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-])=O)[C:5]=1[O:6][CH2:7][C:8](=O)[CH3:9])(=[O:3])[CH3:2].[H][H]>[Ni].C(O)C>[F:15][C:14]1[CH:13]=[CH:12][C:11]2[NH:16][CH:8]([CH3:9])[CH2:7][O:6][C:5]=2[C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1C(C)=O
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1c(F)ccc2c1OCC(C)N2
Yield: 67.7 %

Procedure:
A mixture of 4.98 g (19.5 mmole) of 1-(2-acetyl-3-fluoro-6-nitrophenoxy)-2-propanone, 100 ml of 95% ethanol and 1 g of Raney nickel was shaken in an atmosphere of hydrogen at 4.5×105Pa at room temperature for 18 hours. The reaction was filtered and the solvent removed at reduced pressure. The residue was chromatographed on silica, with hexane:ether (1:1) to give 2.76 g of 1-(7-fluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazin-8-yl)ethanone.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:33])[CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10][C:5]2=[CH:4][CH:3]=1.[Li+].[Cl-].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>C1COCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([NH:11][C:9]3[S:8][C:6]4[C:5]([N:10]=3)=[CH:4][CH:3]=[C:2]([CH:36]=[CH2:37])[N:7]=4)=[O:33])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: O=C(Nc1nc2ccc(Br)nc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 66.7 %

Procedure:
To mixture of N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-2-(4-cyclopropanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (Example-A95) (0.135 g, 0.24 mmol), Pd(PPh3)4 (0.014 g, 0.012 mmol) and LiCl (0.031 g, 0.73 mmol) in THF:DMF (1:1, 5 mL) under inert atmosphere was added tributyl(vinyl)stannane (0.23 g, 0.73 mmol) and heated under reflux for 8 hrs. Solvent was removed in vacuo and taken into brine and extracted with ethyl acetate (3×5 mL), washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford titled compound (0.080 g)
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH3:27])=[O:12])=[O:8].BrN1C(=O)CCC1=O.[I:40]N1C(=O)CCC1=O>>[I:40][C:31]1[C:9]([C:7]([NH:6][CH2:5][CH:4]=[N:3][O:2][CH3:1])=[O:8])=[C:10]([CH:28]=[CH:29][CH:30]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH3:27])=[O:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CON=CCNC(=O)c1ccccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1C
Agent: O=C1CCC(=O)N1Br
Product: CON=CCNC(=O)c1c(I)cccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1C
Yield: 53 %

Procedure:
2-(2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-pentafluoroethylbenzanilide was treated in the same manner as in Example 36, except that the N-bromosuccinimide was replaced with N-iodosuccinimide, to obtain 3-iodo-2-(2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-pentafluoroethylbenzanilide (yield 53%, melting point 110° C.). Regioselectivity of iodination into the 3-position was 100%.
Reaction SMILES: ClC(OCC)=O.[C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(O)=[O:8].C(N(CC)CC)C.Cl.[CH2:53]([O:60][C:61](=[O:67])[C@@H:62]1[CH2:66][CH2:65][CH2:64][NH:63]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([CH2:53][O:60][C:61]([CH:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:7]([C@@H:10]2[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]2[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:8])=[O:67])[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)N1CCCC1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a -5° C. methylene chloride (1 mL) solution of ethyl chloroformate (0.12 g, 1.1 mmol) was added a methylene chloride solution of compound 29 (0.35 g, 0.7 mmol), followed by the addition of triethylamine (0.112 g, 1.1 mmol). The resultant reaction mixture was stirred for 1 h between -5° C. and 5° C. Triethylamine (0.11 g, 1.1 mmol) and proline benzylester hydrochloride (260 mg, 1.1 mmol) was added, and the solution was stirred between -5° C. to 5° C. for an additional 15 min and for 16 h at room temperature. The solution was washed with saturated aqueous NaHCO3 solution, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:EtOAc/8:2) to afford 70 mg (14%) of the title compound.
Reaction SMILES: [C:1](Cl)(=O)C.[CH:5]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH3:1][O:13][C:12]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14]
Reactant: O=C(O)C1CCCCCC1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C1CCCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methanol (20 ml) was cooled to 0° C. and acetyl chloride (2.0 ml) was added. The mixture was stirred for 10 minutes and cycloheptanecarboxylic acid (2.0 ml) was added. The cooling bath was removed and the mixture was heated to reflux and stirred for 8 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc. The organic layer washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated under reduced pressure, affording cycloheptanecarboxylic acid methylester (1.82 g) as a pale yellow liquid. This methylester intermediate (1.8 g) was dissolved in THF (25 ml) and cooled to −40° C. Lithium aluminium hydride (11.5 ml of a 1.0 M sol. in THF) was added drop-wise. The reaction mixture was allowed slowly to warm to 0° C. and stirring was continued at this temperature for 3 hours. Aqueous sodium hydroxide (5 ml of a 1 M sol.) was added and the mixture was filtrated. The filtrate was evaporated under reduced pressure and re-dissolved in EtOAc (20 ml), dried (Na2SO4) and evaporated under reduced pressure, and gave cycloheptyl-methanol (1.37 g) as a clear colourless oil. This alcohol intermediate was converted into the title compound, as described for preparation 66, using N-hydroxyphthalimide. 13C-NMR (DMSO-d6) δ 78.8, 37.1, 30.0, 27.9, 25.6.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[CH:13]3[CH2:17][C:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:3]2[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=2[CH3:1])[C:6]([NH:8][CH:9]2[C:14]([CH3:15])([CH3:16])[CH:13]3[CH2:17][C:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])(=[O:23])=[O:22])[CH2:25][CH2:26]1)(=[O:33])=[O:32]
Reactant: Cc1ccc(C(=O)NC2C3(C)CCC(C3)C2(C)C)cc1S(=O)(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2C3(C)CCC(C3)C2(C)C)cc1S(=O)(=O)N1CCN(S(C)(=O)=O)CC1
Yield: 44 %

Procedure:
Compounds 32 was prepared from 117 mg 29 by stirring in 5 mL dry dichloromethane adding 100 μl N,N-diisopropylethylamine and 20 μl methyl sulfonyl chloride overnight at room temperature. After aqueous work-up the product was isolated by preparative HPLC chromatography and 48 mg of an off white solid was obtained (44% yield). MS (M−1)=496.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[F:31][C:32]([F:43])([F:42])[CH:33]([F:41])[C:34]([F:40])([F:39])[S:35]([OH:38])(=[O:37])=[O:36]>ClCCl.O>[F:43][C:32]([F:31])([F:42])[CH:33]([F:41])[C:34]([F:39])([F:40])[S:35]([O-:38])(=[O:36])=[O:37].[CH3:11][C:5]1[CH:10]=[CH:9][C:8]([S+:2]([CH3:4])[CH3:1])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Reactant: CS(C)=O
Reactant: Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: Cc1ccc([S+](C)C)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Temperature: 0 °C
Yield: 169.1 %

Procedure:
A mixture of 7.81 g (10.0 mmol) of dimethyl sulfoxide with 9.21 g (10.0 mmol) of toluene was placed in a 200 ml flask. Then 40 ml of a previously prepared phosphorus pentaoxide/metanesulfonic acid reagent (prepared by dissolving 36 g of phosphorus pentaoxide in 360 g of methanesulfonic acid) was added thereto while stirring with a magnetic stirrer. A slight exothermic reaction occurred. The system was stirred at room temperature for 6 hours. The reaction mixture was poured into 150 ml of water and 150 g of ice. The slightly suspended solution was filtered, followed by addition of 23.2 g (10.0 mmol) of 3,3,3,2,1,1-hexafluoropropane sulfonic acid to yield a colorless oil. The oil was stirred for 1 hour, and 200 ml of dichloromethane was added thereto. The mixture was extracted. The organic phase was washed several times with water, and then dried. The solvent was removed by distillation. The oily residue was recrystallized from isopropyl alcohol to give 6.5 g of the contemplated material. The structure was confirmed by 1H-NMR (CDCl3) with δ=2.41 (s, 3H), 3.46 (s, 6H), 5.32-5.56 (d[m], 1H), 7.42-7.45 (d, 2H), 7.50-7.53 (d, 2H) ppm.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=[C:18]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:17]=1.C(N(CC)CC)C.O>O1CCCC1>[C:2]1([CH:8]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:9]2[C:16]2[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[N:17]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCOCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCOCCC2c2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a suspension of 5-phenyl-[1,4]oxazepane hydrochloride (0.07 g, 0.33 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.07 g, 0.30 mmol) in tetrahydrofuran (2 mL) in a sealed tube was added triethylamine (0.14 mL) at room temperature. The mixture was heated to 150° C. under microwave irradiation and stirred for 15 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (chloroform/methano=10/1 as an eluant) to yield 2-(5-phenyl-[1,4]oxazepane-4-yl)-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A071) (0.07 g, 0.20 mmol, 66%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)[CH:16]([CH3:18])[CH3:17].[OH-].[NH4+:27]>>[CH:16]([C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]([C:10]2[CH:13]=[CH:14][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[C:8]([CH:7]=[CH:1][CH2:2][CH2:3][CH3:4])=[C:9]([CH:10]([CH3:13])[CH3:11])[N:27]=1)([CH3:18])[CH3:17]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [OH-]
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(-c2ccccc2)cc1

Procedure:
Prepared from 4-phenylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDCl3): δ 0.73 (t, J=7.4 Hz, 3 H), 0.93 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 14 H), 1.97 (tdd, J=7.0, 7.0, 1.1 Hz, 2 H), 3.10 (m, 1 H), 3.45 (m, 1 H), 4.0 (q, J=7.4 Hz, 2 H), 5.40 (m, 1 H), 6.10 (dt, J=16.2, 1.1 Hz, 1 H), 7.20-7.70 (m, 9 H). mp 104-106° C.