Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[N:11]=[CH:10]1)=[O:4].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:13]=[C:12]([NH:14][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=2)[CH2:33][CH2:34][CH3:35])[N:11]=[CH:10]1)=[O:4]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C1CCC1n1cnc([N+](=O)[O-])c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCC2C(=O)OC)cn1

Procedure:
2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl ester was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 463.1 m/z (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:65][C:66]1[CH:78]=[CH:77][C:69]([CH2:70][C@@H:71]2[CH2:76][CH2:75][CH2:74][NH:73][CH2:72]2)=[CH:68][CH:67]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([N:73]2[CH2:74][CH2:75][CH2:76][C@@H:71]([CH2:70][C:69]3[CH:68]=[CH:67][C:66]([F:65])=[CH:78][CH:77]=3)[CH2:72]2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (80 mg, 240 μmol) in methylene chloride (5 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (151 mg, 290 μmol) and triethylamine (77 μL, 550 μmol) and stirred for 5 minutes. A solution of the (S)-3-(4-flourobenzyl)-piperdine prepared above in methylene chloride (5 mL) was added and the mixture was stirred at room temperature. After 18 h, the mixture was washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes) to provide the product as a gum (100 mg, 82%).
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]([OH:14])[CH3:13])[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:14][CH:12]([CH:9]1[CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10]1)[CH3:13])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1CCC(OC(C)(C)C)CC1
Product: CC(=O)OC(C)C1CCC(OC(C)(C)C)CC1
Temperature: 20 °C

Procedure:
A mixture of 200 g (1 mole) of 1-(p-tert.-butoxycyclohexyl)-ethan-1-ol and 306 g (3 moles) of acetic anhydride was refluxed for 30 minutes. 260 g of a mixture of acetic acid and excess acetic anhydride were distilled off in the course of 3 hours under atmospheric pressure, and the residual acetic anhydride was then removed under reduced pressure (20 mbar). The residue was cooled to 20° C., washed with water and aqueous bicarbonate solution and again with water and then fractionated to give 218 g of a fraction which distilled over at 90° C./0.1 mbar and had an interesting herbaceous fruity note.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:17]1[O:20][CH:18]1[CH3:19]>C(#N)C>[OH:20][CH:18]([CH3:19])[CH2:17][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC1CO1
Solvent: CC#N
Product: CC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 68.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazol (1.5 g, 6.8 mmol) and propylene oxide; (2 g, 34.4 mmol) in 25 ml acetonitrile was heated to 50° C. in an autoclave for 3 days. The cooled reaction was concentrated in vacuo and purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fraction afforded 1.3 g (68.4%) of 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6-fluoro-1, 2-benzisoxazole. M.p. 45°-47° C. MS (70 eV): m/z 278 (M+, 18%), 233 (100), 190 (28), 109 (12), 96 (70), 82 (25), 68 (14), 55 (22).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][C@H:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][C@H:12]1[CH2:13][O:14][C:27]([CH3:32])([CH3:28])[N:15]1[C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@@H](COCc1ccccc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 3.51 g of tert-butyl (3(S)-benzyloxymethyl-1(S)-hydroxymethyl-4-methyl-pentyl)carbamate in 20 ml of dichloromethane is cooled to 0° C. and admixed successively with 0.076 g of p-toluenesulphonic acid monohydrate and 2.6 ml of 2-methoxypropene. The reaction mixture is stirred at room temperature for another 16 hours and subsequently poured onto 1M sodium hydrogencarbonate solution, extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf=0.42 (1:4 EtOAc-heptane); Rt=6.20 (gradient I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1nc2ccc(Br)cn2n1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((AS), 5.0 g; 23.47 mmol; 1.0 eq.) and benzoyl chloride (6.57 g; 46.9 mmol; 2.0 eq.) as a white powder (6.5 g, 87%). HPLC, Rt: 2.49 min. (purity 97.1%). LC/MS, M+(ESI): 317.0, M−(ESI): 316.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:20][CH:19]=1)([OH:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Reactant: COc1ccc(Br)c(OC)c1
Product: COc1ccc(C(O)(c2ccc(C(C)C)cc2)C(C)C)c(OC)c1
Yield: 56 %

Procedure:
Using 1-bromo-2,4-dimethoxybenzene and 1-(4-isopropylphenyl)-2-methylpropan-1-one the title compound was obtained in the same manner as in Reference Example 6. Yield 56%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([N:14](S(CCC)(=O)=O)[S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])=[CH:12][CH:11]=[C:10]([F:27])[C:5]=1[C:6]([O:8]C)=[O:7]>C1COCC1.CO>[F:3][C:4]1[C:13]([NH:14][S:15]([CH2:18][CH2:19][CH3:20])(=[O:16])=[O:17])=[CH:12][CH:11]=[C:10]([F:27])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A 1N aqueous NaOH solution (150 mL, 150 mmol) was added to a solution of methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (20.0 g, 50.1 mmol) in 4:1 THF/MeOH (250 mL, 0.2M). The reaction mixture was stirred at room temperature overnight. The majority of the organic solvents were then removed in vacuo (water bath temperature 35° C.). 1N HCl (150 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with water (4×50 mL). The material was then washed with Et2O (4×15 mL) to give 2,6-difluoro-3-(propylsulfonamido)benzoic acid as a solid (10.7 g, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ 9.74 (s, 1H), 7.57-7.50 (m, 1H), 7.23-7.17 (m, 1H), 3.11-3.06 (m, 2H), 1.79-1.69 (m, 2H), 0.98 (t, J=7.4 Hz, 3H). m/z (APCI-neg) M−1=278.0.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.C(=O)([O-])[O-:10].[K+].[K+]>CO>[OH:10][CH:2]1[CH2:3][CH2:4][CH:5]2[CH:1]1[CH2:8][CH2:7][CH2:6]2
Reactant: C1CC2CCCC2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CCC2CCCC12

Procedure:
A mixture of (E)-6-acetoxy-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]bicyclo[3,3,0]octane (0.4 g; prepared as described in Example 31 and predominantly in the 2β-configuration), potassium carbonate (0.15 g) and methanol (10 ml) was heated at 50° C. for 8 hours. The mixture was then cooled and concentrated in vacuo. The resulting residue was extracted with dichloromethane (3×5 ml). Concentration in vacuo of the combined extracts gave (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-6-hydroxybicyclo[3,3,0]octane, predominantly in the 2β-configuration, in the form of an oil (0.36 g), sufficiently pure enough in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(C(c2ccccc2)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A solution of 4-(4-chlorobenzhydryl)piperazine 1 (2 mmols) and chloro-(4-chlorophenyl)phenylmethane 21 (Aldrich, 2 mmols) in methylene chloride (10 mL) and Et3N (0.3 mL) is stirred under an inert atmosphere. The solution is warmed and the course of the reaction is followed by TLC. When the reaction is complete, dil. aq. Na2CO3 is added to the solution, shaken, and the layers are separated. The aqueous layer is extracted with additional CH2Cl2, the combined organic extracts are washed with half-saturated brine, dried (Na2SO4), filtered and concentrated under reduced pressure giving the crude product. The desired compound 1,4-bis-(4-chlorobenzhydryl)piperazine 22 is obtained by purification of the crude product with the use of HPLC.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[S-:25][C:26]#[N:27].[K+].P(OP(OP(OP(O)(O)=O)(O)=O)(O)=O)(O)(O)=O.Cl(O)(=O)(=O)=O>O1CCCC1.O>[OH:1][C@@H:3]1[C@@H:2]([S:25][C:26]#[N:27])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: N#C[S-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](SC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg.) and potassium thiocyanate (2 g.) in dry tetrahydrofuran (40 ml.) were treated with tetraphosphoric acid (about 2 ml.), and the reaction was stirred at room temperature for 2 hours. Perchloric acid (60%, 0.1 ml.) was added, and after a further 30 minutes the solution was diluted with water and extracted with ether. The extract was washed with water, dried over sodium sulphate and evaporated to give a colourless oil which was purified by preparative tlc and recrystallisation from acetone/petrol to give the title compound, as white prisms m.p. 165°-170° [α]D + 78°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[S:7][C:6]=2[C:17]=1[CH3:18].[C:21](OC(=O)C)(=[O:23])[CH3:22].C1C=CC=CC=1>N1C=CC=CC=1>[C:21]([O:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[S:7][C:6]=2[C:17]=1[CH3:18])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COCOCCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COCOCCCC1Oc2c(C)c(C)c(OC(C)=O)c(C)c2S1

Procedure:
100 mg of 5-hydroxy-2-(3-methoxymethoxypropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 83) were dissolved in 1 ml of pyridine, and 50 mg of acetic anhydride were added. The reaction mixture was allowed to react for 20 hours at room temperature. Benzene was then added to the reaction mixture, and the benzene solution was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with a 20:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])[C:9]1=[O:23])=[O:6])C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:49][C:50]1[CH:59]=[C:58]2[C:53]([C:54]([N:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)=[CH:55][C:56]([NH2:60])=[N:57]2)=[CH:52][CH:51]=1>>[NH2:60][C:56]1[CH:55]=[C:54]([N:61]2[CH2:62][CH2:63][N:64]([C:5]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[O:16])[C:9]3=[O:23])=[O:6])[CH2:65][CH2:66]2)[C:53]2[C:58](=[CH:59][C:50]([Cl:49])=[CH:51][CH:52]=2)[N:57]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)OCC(F)(F)F)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)OCC(F)(F)F)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid, 2,2,2-trifluoroethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 543 (M++1). 1H NMR (DMSO+TFA): δ 1.32–1.45 (m, 1H), 1.56˜1.90 (m, 5H), 3.26 (m, 4H), 3.54–3.66 (m, 5H), 4.15 (m, 1H), 4.68 (br.d, 1H), 4.83 (m, 2H), 6.32 (s, 1H), 7.42 (dd, 1H), 7.60 (d, 1H), 7.90 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:9]2[C:8]3[C:13](=[CH:14][C:15]([F:16])=[C:6]([NH:5][CH2:4][C:3]4[C:2]([CH3:1])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:32])[CH:7]=3)[N:12]=[C:11]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:10]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1cccc(C)c1CNc1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C24H23FN6O2, 446.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19].[Cl:27][C:28]([Cl:33])([Cl:32])[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][C:28]([Cl:33])([Cl:32])[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:30]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of intermediate 11 (0.0536 mol) in DCM (200 ml) was cooled to 5° C. under N2 flow. A solution of trichloro-acetylchloride (0.0643 mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 30 minutes. A solution of triethylamine (0.0643 mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour then at room temperature for 2 hours, poured out into ice water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 27.4 g (quantitative) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methoxybenzoyl)phenyl]-acetamide (intermediate 12).
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1.Cl[SiH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1>>[F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([Si@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH2:8][CH2:7]1
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1
Reactant: FC(F)CCCC1CCC(Br)CC1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: Fc1ccc([C@H]2CC[Si@H]([C@H]3CC[C@H](CCCC(F)F)CC3)CC2)cc1

Procedure:
The above compound was obtained in the same manner as Example 6, using 4-(4, 4-difluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-fluorobenzene instead of 4-(4-fluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-l, 2-difluorobenzene, respectively.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:14][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH:1]=[O:16])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)C(=O)N(C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCc2ccc(C=O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of 7-ethenyl-2-methyl-3,4-dihydro-1(2H)-isoquinolinone (181 mg, 0.968 mmol) in 1,4-dioxane (I 5 ml) and water (3 ml) at 0° C. was added sodium periodate (476 mg, 2.226 mmol) and osmium tetroxide (1.1 ml of a 4% aqueous solution). The reaction mixture was warmed to room temperature and stirred for 0.5 h before evaporation of the reaction mixture. The residue was dissolved in 1,4-dioxane (20 ml) and evaporated again. The mixture was then dissolved in dichloromethane (100 ml), dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% Ethyl Acetate/Hexane, gave the product (136 mg, 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:30]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]([Br:30])[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (5.0 g, 15.2 mmol; Example 32, step 5) and sodium bicarbonate (19.2 g, 228 mmol) in dichloromethane (150 mL) at 0° C., a solution of bromine in dichloromethane (0.5 M, 32 mL, 16 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexane-ethyl acetate gradient to provide the titled product.
Reaction SMILES: ClC1C=C[CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17]C(C)(C)C(O)=O)=[CH:14][N:15]=1.BrCC1CC1.C([O:43][C:44](=[O:53])CSC1SC(N)=NC=1)C>>[CH:3]1([CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:9](=[O:24])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:44]([OH:53])=[O:43])=[CH:14][N:15]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: BrCC1CC1
Product: C[C@H]1CC[C@H](N(CCOCC2CC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using bromomethyl-cyclopropane and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[NH4+].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)c(C)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1c[n+]([O-])c(C)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The above 3-chloro-2,5-dimethylpyridine 1-oxide (1.20 g) was dissolved in concentrated sulfuric acid (6 mL), and a mixture of fuming nitric acid (9.5 mL) and fuming sulfuric acid (5.5 mL) was added dropwise over 25 minutes. After stirring in that state for 30 minutes, the mixture was stirred at 90° C. for two hours. The reaction solution was left to cool, and then introduced into ice water and neutralized with ammonium carbonate with stirring at room temperature. The insoluble matter was separated off by filtration, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (1.11 g, 72%) as a solid.