Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([Li])[CH2:13][CH2:14]C.CC1(C)CCCC(C)(C)N1>>[CH2:14]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([O:10][CH3:11])=[N:5][C:6]=1[O:8][CH3:9])[CH:13]=[CH2:12]
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Product: C=CCc1c(Cl)nc(OC)nc1OC

Procedure:
Synthesis of 2,4-dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 33 could also be performed according to the pathway described on Scheme 12. 4-Chloro-2,6-dimethoxypyrimidine 40 could be deprotonated with a strong base, such as n-butyllithium or 2,2,6,6-tetramethylpiperidine, and quenched with allyl bromide to give 5-allyl-4-chloro-2,6-dimethoxypyrimidine 41. Nencka, R.; Votruba, I.; H{hacek over (r)}ebabecký, H.; Jansa, P.; Tlou{hacek over (s)}t'ová, E.; Horská, K.; Masojídková, M.; Holý, A. J. Med. Chem. 2007, 50, 6016-6023. The latter compound can react with α-styrylborinic acids in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, to provide compounds of formula 42 which can undergo ring closure olefin metathesis under Grubbs conditions to form 2,4-dimethoxy-7-aryl-5H-cyclopenta[d]pyrimidines 43. Grubbs, R. H. Handbook of Metathesis, 2003, First Edition, Wiley-VCH. The double bond in compounds 43 can be reduced to give 2,4-dimethoxy-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 44, which upon acid-catalyzed hydrolysis, followed by chlorination with phosphorus oxychloride afford intermediates 33.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13](O)=O)([O-:3])=[O:2].CC1C([N+]([O-])=O)=C(C=CC=1)C(O)=O>>[CH3:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Product: Cc1c(C(=O)O)cccc1[N+](=O)[O-]

Procedure:
The disadvantage of this synthesis route is the poor availability of the starting substance 2-methyl-3-nitrobenzoic acid. In Kulic et al., J. Gen. Chem. USSR (Engl.), 60, 2118 (1990), the oxidation of 2,3-dimethylnitrobenzene to 2-methyl-3-nitrobenzoic acid is carried out using aqueous potassium permanganate in the presence of a phase-transfer catalyst at 75° C. In this process, 2-methyl-3-nitrobenzoic acid is not obtained as a pure product, but as a mixture with 3-nitrophthalic acid and smaller amounts of 3-methyl-2-nitrobenzoic acid. A complicated purification is necessary in order to obtain pure 2-methyl-3-nitrobenzoic acid from the crude product. This is at the expense of the yield. A further serious disadvantage is the extremely poor space yield of the oxidation reaction. Per 100 ml of water, only 2.4 g of 2,3-dimethylnitrobenzene are employed (see p. 2121). Moreover, manganese dioxide, which has to be disposed of, is formed during the permanganate oxidation.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:31]([OH:34])[C:32]#[CH:33].C(NCC)C>[Cu]I.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][OH:34])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(I)cc34)CC2)cc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCO)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 4-(6-iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (1.056 g, 2.05 mmol), as prepared in Example 11d, CuI (3.9 mg, 20.5 μmol), trans-PdCl2[P(C6H5)3]2 (26.8 mg, 38.2 μmol), propargyl alcohol (139 μL, 2.36 mmol), and diethylamine (3.4 mL) was flushed with a stream of argon for 30 s, and then quickly sealed and vigorously stirred at rt under argon for 5 h. The resulting dark brown bilayer was concentrated under reduced pressure at rt, dissolved in DCM (10 mL), and vigorously shaken with 0.75 M EDTA (tetrasodium salt) (1×2 mL). The light green aqueous layer was extracted with DCM (1×10 mL), the organic layers were combined, dried (Na2SO4), and concentrated to give a beige foam soluble in 9:1 EtOAc/DCM (˜5 mL). Flash chromatography (1:9 hex/EtOAc→EtOAc) provided the title compound as a yellow foam (825 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.26 (d, 1H), 8.01 (d, 1H), 7.87 (dd, 1H), 7.25 (m, 2H), 6.85 (m, 2H), 6.33 (br s, 1H), 4.59 (d, 2H), 4.48 (heptet, 1H), 4.32-4.23 (m, 2H), 3.71 (m, 1H), 3.22-3.10 (m, 2H), 2.21-1.94 (m, 5H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 444.2, found 445.2 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:25].C(O)(=O)C.Cl>O>[CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:25]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(/C=C/C(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Yield: 76.4 %

Procedure:
A solution of ethyl (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoate (4.0 g) in a mixture of glacial acetic acid (50 ml) and concentrated hydrochloric acid (50 ml) was heated at reflux for 2 hours and then poured onto a mixture of ice and water (100 g). The resulting white solid was filtered off and crystallised from ethanol, to give (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoic acid (2.8 g) in the form of white crystals, m.p.266°-268° C. [Elemental analysis: C,74.3; H,5.0; N,4.2%; calculated: C,74.7; H,4.95; N,4.59%].
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Br-].[CH2:31]([Zn+])[CH2:32][CH3:33]>C1(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)C=CC=CC=1.C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:24]=[N:25][C:26]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCC[Zn+]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(Cl)nc3)c2C#N)CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C#N)cn1

Procedure:
In a 25 mL round-bottomed flask fitted with a condenser and N2 inlet was placed 4-[6-(6-chloro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (100 mg, 1.3 mmol), n-propylzinc bromide (0.5M in THF, 0.72 mL), tetrakis(triphenylphosphino)palladium (28 mg, 0.024 mmol), and THF (3.5 mL). The reaction mixture was refluxed overnight under N2 atmosphere. The product was purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.03 (t, 3H), 1.26 (d, 6H), 1.85 (m, 4H), 1.98 (m, 2H), 3.04 (t, 2H), 3.44 (m, 2H), 3.77 (m, 2H), 4.94 (m, 1H), 5.46 (m, 1H), 7.57 (d, 1H), 8.34 (s, 1H), 8.51 (s, 1H), 8.56 (d, 1H), 9.42 (s, 1H). Exact mass calculated for C22H28N6O3 424.22, found 425.2 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[CH3:17][O:16][C:14](=[O:15])[O:10][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: Cc1ccc(O)c(F)c1F
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A solution of 2,3-difluoro-4-methyl phenol (3.3 g, 22.89 mmol) in THF (30 ml) was cooled to 0° C. in an ice bath, and 60% NaH (0.916 g, 22.9 mmol) was added. When the gas evolution ceased, methyl chloroformate (1.76 ml, 22.9 mmol) was added. The ice-bath was removed and the mixture was stirred at room temperature for three hours. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 9:1) gave 3.85 g (83%) of carbonic acid 2,3-difluoro-4-methyl-phenyl ester methyl ester as a clear oil.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C([O:57][CH2:58]C)C.[O:60]1CCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:11]1([C:8]2[S:9][C:10]3[C:2]([C:58]([OH:57])=[O:60])=[CH:3][CH:4]=[C:5]([O:17][CH3:18])[C:6]=3[N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: COc1ccc(Br)c2sc(N3CCCCC3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2sc(N3CCCCC3)nc12

Procedure:
Starting from 7-bromo-2-(piperidin-1-yl)-4-methoxybenzothiazole (1.4 g), palladium (II) acetate (100 mg), bis-diphenylphosphinopropane (350 mg), and triethylamine (6 ml) in tetrahydrofuran (200 ml) and water (20 ml). Trituration ofthe residue with diethyl ether yielded the title compound as a yellow solid (700 mg). TLC Rf 0.66 (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28](O)=[O:29])=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:37][CH2:36][CH2:35][CH2:34][NH:33][C:28]([C:27]1[C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:32][C:24]=2[S:25][C:26]=1[CH3:31])=[O:29]
Reactant: NCCCO
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCCO)c(C)sc5c4)c3s2)C1
Yield: 23.3 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with 3-amino-1-propanol (106 μL, 1.39 mmole), N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to give a yellow solid (34 mg, 23%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.65 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.07 Hz), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.07, 8.85 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz), 4.13–3.82 (3H, m), 3.62 (2H, m), 3.50 (2H, m), 3.39–3.30 (2H, m), 3.27, 3.24 (3H, s), 2.60 (3H, s), 2.18–1.93 (2H, m), 1.71 (2H, quintet, J=6.6 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][NH:15]1)=[O:13].[N:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[C:21]=[O:22].O>ClCCl>[CH3:10][O:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:21](=[O:22])[NH:20][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=1)=[O:13]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Diisopropylethylamine (0.782 g, 5.5 mmol) was dropped into a suspension of compound (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 5.5 mmol) in anhydrous dichloromethane (50 mL), the mixture was stirred at room temperature for 10 minutes. 1-isocyanato-4-(trifluoromethoxy)benzene (1.116 g, 5.5 mmol) was added to the suspension and the mixture was continued to be stirred for 2 hours at room temperature. The mixture was poured into water (50 mL), the resulting mixture was filtrated. The liquid was extracted with dichloromethane (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue combined with the filter cake yielded 1.86 g (97%) of the target compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 2H, J=9.0 Hz), 7.14 (d, 2H, J=8.7 Hz), 6.59 (s, 1H), 4.64 (t, 2H, J=7.5 Hz), 3.78-3.73, (m, 4H), 3.59 (d, 1H, J=9.9 Hz), 2.36-2.21 (m, 2H); LC-MS: 349.1 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[O:30]C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[OH:30]
Reactant: COc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A solution of 6-chloro-12-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (157 mg, 0.34 mmol) in methylene chloride (2.5 mL) was cooled to −78° C. and 1 M boron tribromide in methylene chloride (1.68 mL, 1.68 mmol) was added slowly. The mixture was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to −78° C. and saturated sodium bicarbonate solution was added. The resulting suspension was filtered and the collected solid was washed with water and ethyl acetate to give the desired compound (113 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.25 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.48 (s, 1H), 7.08 (m, 1H), 6.81 (m, 3H), 6.71 (d, 1H), 2.82 (s, 4H). LCMS for C18H16ClN4O (M+H)+: m/z=339.1.
Reaction SMILES: C([O:8][C:9]1([CH3:30])[CH2:18][CH2:17][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:21]=[C:12]3[C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>CN(C=O)C.CCO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:19](=[O:29])[C:13]3=[CH:14][NH:15][C:16]4[CH2:17][CH2:18][C:9]([OH:8])([CH3:30])[CH2:10][C:11]=4[C:12]3=[N:21]2)=[CH:23][CH:24]=1
Reactant: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Reactant: [H][H]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(O)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
8-Benzyloxy-2-p-chlorophenyl-8-methy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (4 g) is dissolved in 200 mL of a 1:1 mixture of DMF/EtOH and subjected to catalytic hydrogenation with 5% palladiium on carbon (1 g) for 24 hours under 1 atm. of hydrogen. After the reaction is over, the catalyst is filtered off, the filtrate is evaporated, and the dried residue is triturated with EtOH to yield 2-p-chlorophenyl-8-hydroxy-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[S:32]([CH3:31])(=[O:34])=[O:33])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the product from Example 1 (70 mg) dissolved in DCM was added methanesulfonyl chloride (16 μl) and TEA (28.3 μl) under nitrogen. The resulting solution was stirred at rt for 16 h. The solvents were evaporated, the residue redissolved in MeOH and the crude product was purified by RPHPLC to afford the title compound 32 mg.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7]C=[CH:5][CH:4]=1.[CH2:11]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH:23]N1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)S1(=O)=O>>[C:11]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:34]1([OH:35])[CH2:33][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCCCCCCCCCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1O
Reactant: FC(F)(F)c1ccccc1
Product: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1
Yield: 22 %
Yield: 5.5 %

Procedure:
To 9 ml of trifluorotoluene was added 504 mg (3.0 mmol) of cyclododecane, 60 mg (0.3 (mmol) of N-hydroxysaccharin and 5.3 mg (0.015 mmol) of acetylacetonatocobalt Co(acac)3. The resultant mixture was stirred under an oxygen atmosphere at a temperature of 100° C. for 4 hours. The products in the reaction mixture were analysed by gas chromatography, with cyclododecane being transformed, with a conversion of 34.5%, into cyclododecanone (selectivity 64%, yield 22%), cyclododecanol (selectivity 16.5%, yield 5.5%) and dodecanediacid (selectivity 5%, yield 2%).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[OH:6][NH3+:7].O[NH3+].[OH-].[Na+].[CH2:12]([OH:14])[CH3:13]>C(O)(=O)C>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:7][OH:6].[CH2:12]([OH:14])[CH3:13]
Reactant: O=S(=O)([O-])[O-]
Reactant: [NH3+]O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NO
Product: O=S(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture was prepared from 25% aqueous hydroxylammonium sulfate (39.0 g, 0.060 mol) and 50% aqueous sodium hydroxide (9.6 g, 0.12 mol). 40 mL of ethanol was then added and the mixture was allowed to cool to room temperature and filtered to remove sodium sulfate. The filtered solution was placed in a 250-mL, 3-necked flask equipped with a reflux condenser, thermometer, heating mantle, stirrer, pH electrode, and dropping funnel. Then an α,β-unsaturated ester (ethyl crotonate or ethyl acrylate) (0.10 mole) was added and the mixture was stirred at room temperature for 60 minutes. Then an α,β-unsaturated carbonyl compound (0.125 mole) was added all at once. About 10 mL of acetic acid was added to lower the pH to below 4.0 and the reaction mixture was heated to reflux for 3 to 5 hours.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])[S:3][C:4]=4[CH:10]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.4 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (65 μL, 0.715 mmol), and the mixture was stirred at room temperature for 10 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (30 μL, 0.33 mmol), and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (140 mg, 40%) as a colorless solid.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)[C@H](NC(=O)NC1CCCC1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCC1)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 (25 mL) was added TFA (4 mL) and triethylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylacetic acid as a white solid (0.69 g, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H) 3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LC-MS: Anal. Calcd. for C14H18N2O3: 262.31. found: 263.15 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=1.24 min, 100% homogeneity index.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1>N1C=CC=CC=1>[C:1]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CCC[C@@H](N)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CCC[C@@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Acetic anhydride (1.20 ml, 12.7 mmol) was added to a stirred solution of cis-methyl 3-aminocyclohexanecarboxylate (0.40 g, 2.54 mmol) in pyridine (10 ml) under an atmosphere of argon and stirred for 3 h at room temperature. The excess pyridine was removed under vacuo and the resulting residue was partitioned between DCM and saturated sodium bicarbonate solution. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford cis-methyl 3-acetamidocyclohexanecarboxylate (350 mg, 69.0%) as a colorless liquid.