Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([OH:15])=O)[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[NH2:47][C:48]1[CH:81]=[CH:80][C:51]([O:52][C:53]2[CH:58]=[CH:57][N:56]=[C:55]3[N:59]([CH2:71][C:72]4[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=4)[N:60]=[C:61]([N:62]4[CH2:67][CH2:66][CH:65]([N:68]([CH3:70])[CH3:69])[CH2:64][CH2:63]4)[C:54]=23)=[C:50]([F:82])[CH:49]=1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([NH:47][C:48]2[CH:81]=[CH:80][C:51]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]4[N:59]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH3:79])=[CH:76][CH:77]=5)[N:60]=[C:61]([N:62]5[CH2:63][CH2:64][CH:65]([N:68]([CH3:70])[CH3:69])[CH2:66][CH2:67]5)[C:54]=34)=[C:50]([F:82])[CH:49]=2)=[O:15])[CH2:11][CH2:12]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1(c2nc3ccccc3o2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)C5(c6nc7ccccc7o6)CC5)cc4F)ccnc32)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a stirred solution of 1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylic acid (3.8 mg, 0.019 mmol) in 150 μL dichloromethane at room temperature under nitrogen was added DIEA (8 μL, 0.047 mmol) followed by EDCI (4.5 mg, 0.024 mmol) and HOBT-H2O (3.6 mg, 0.024 mmol). After 15 minutes, a solution of 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (7.7 mg, 0.016 mmol) (prepared in Example 93, Step A) in 150 μL dichloromethane was added. After stirring for 48 hours, the reaction was diluted to 30 mL with dichloromethane and washed with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with a step gradient of dichloromethane (100 mL), 2.5/97.5 MeOH/dichloromethane (100 mL) and 5/95 MeOH/dichloromethane to provide the desired product as a white foam (6.6 mg, 62% yield).
Reaction SMILES: [CH:1]1(C([O-])=O)[C:9]2[C:4](=CC=CC=2)[CH2:3][NH:2]1.O[CH:14]1C[NH:17][C@H:16](C(O)=O)[CH2:15]1.O=C1C[NH:26][C@H](C(O)=O)C1.NN>>[N:2]1([C:14]2[CH:15]=[CH:16][NH:17][N:26]=2)[CH2:1][CH2:9][CH2:4][CH2:3]1
Reactant: O=C1CN[C@H](C(=O)O)C1
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: O=C([O-])C1NCc2ccccc21
Agent: NN
Product: c1cc(N2CCCC2)n[nH]1

Procedure:
Heteroaryl derivatives to replace 1,3-dihydro-2H-isoindole-1-carboxylate may be prepared as outlined in Scheme 2. 4-Hydroxy-(L)-proline derivative D is oxidized to 4-keto-(L)-proline E which is formylated and then treated with an appropriate hydrazine derivative to form pyrrolidinyl-pyrazole F. The ester in F is hydrolyzed and reacted with amino acid C followed by protecting group removal to form G. The pyrrolidine-amine in G is sulfonylated and the ester removed to form the desired product H.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(O)=CC=1>>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([OH:13])(=[O:12])[C:10]([CH3:14])=[CH2:9]
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: COc1ccc(O)cc1
Product: C=C(C)C(=O)O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
For comparison, a monofunctional methacrylate benzophenone was prepared. 2-benzoylbenzoic acid (113.2 g) and 4-methoxyphenol (0.06 g) were heated to 130° C. in a three-neck flask to melt, then air sparge was applied and glycidyl methacrylate (77.5 g) and benzyltriethylammonium chloride (0.20 g) were added under stirring. The reaction mixture was stirred at 120° C. for 21/2 hrs. A viscous resin was obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]CCC.C([Li])CCC.[CH:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:20](=O)[CH:19]=2)=[CH:14][CH:13]=1.[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32]>O1CCCC1>[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[C:15]1([C:18]2[C:19]([CH2:1][CH2:2][CH3:3])=[CH:20][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O+:24]=2)[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CCCCCC
Reactant: O=c1cc(-c2ccccc2)oc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccccc2)[o+]c1-c1ccccc1
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: -20 °C
Yield: 45 %

Procedure:
A 1.7M hexane solution (3.5 ml) containing 6 mmol of n-butyl lithium was added dropwise to 10 ml of an anhydrous tetrahydrofuran solution containing 1.24 g (5 mmol) of 2,6-diphenyl-γ-pyrone which was cooled to -20° C. One hour later, the reaction mixture was poured into 50 ml of a 6 wt% aqueous solution of perchloric acid. The precipitated solid was collected by filtration, dissolved in a small amount of methylene chloride and reprecipitated in diethyl ether. The precipitated yellow solid was separated by filtration and dried to obtain 0.88 g (yield: 45%) of 2,6-diphenyl-3-n-propylpyrylium perchlorate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[OH:12])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[O:12][CH2:17][O:18][CH3:19])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2
Reactant: COCCl
Reactant: CCc1cccc2c(C=O)cc(Cl)c(O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc2c(C=O)cc(Cl)c(OCOC)c12

Procedure:
1.0 g of 3-chloro-5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde, 0.91 ml of chloromethyl methyl ether and 3.5 ml of N,N-diisopropylethylamine were dissolved in 10 ml of dichloromethane, and reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 0.74 g of the captioned compound as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[CH:13]=1)[C:8](O)=[O:9])=[O:4].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:20].[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[C:12]1[CH:11]=[C:7]([C:8](=[O:9])[NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH:6]=[C:5]([CH:13]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2cc(Cl)ccc2Cl)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)ccc2Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
To a mixture of 3-methoxycarbonyl-5-(2,5-dichlorophenyl)benzoic acid (1.0 g), N,N-dimethylethylenediamine (0.223 g) and 1-hydroxybenzotriazole (0.376 g) in N,N-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.533 g) under ice cooling, and then the solution was stirred for five hours at room temperature. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml) and adjusted to pH 10 with 6N aqueous potassium carbonate solution with stirring. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (100 ml) eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired product were collected and evaporated in vacuo. The residue was dissolved in ethanol (8 ml) and added slightly excess 4N hydrogen chloride in dioxane to afford methyl 5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl)benzoate.hydrochloride (0.43 g).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=1)[C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[O-:20].[Na+].[OH-].[Li+]>CO.O>[CH2:1]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=1)[C:14]([NH2:15])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1cc(C#N)ccn1
Reactant: C[O-]
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCOc1cc(C(N)=O)ccn1
Temperature: 25 °C
Yield: 227 %

Procedure:
A solution of 2-(nonyloxy)isonicotinonitrile (250 mg, 1.0 mmol, 1 equiv.) and sodium methoxide (10 mg, 0.1 mmol, 0.1 equiv.) in dry CH3OH (10 ml) was stirred at r.t. for 2.5 h. A solution of lithium hydroxide (24 mg, 1.0 mmol, 1 equiv.) in water (1 ml) was added and the reaction mixture was heated under reflux for 3.5 h. After cooling at r.t., the mixture was poured into water (40 ml). The precipitant solid was filtered and dried in vacuo at 50° C., to give the desired compound as a white solid (60 mg, 23%), mp 108-110° C. HPLC-MS (method 1): m/z 265 [M+H]+, Rt=5.08 min.
Reaction SMILES: [NH2:1]/[C:2](=[N:12]\[OH:13])/[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:14][CH2:15]OC(C)=O.CC[O-].[Na+]>CCO>[CH3:14][C:15]1[O:13][N:12]=[C:2]([CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])[N:1]=1
Reactant: CC(C)(C)OC(=O)NC/C(N)=N/O
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CNC(=O)OC(C)(C)C)no1
Yield: 93.8 %

Procedure:
To a stirred solution of (Z)-tert-butyl 2-amino-2-(hydroxyimino)ethylcarbamate (945 mg, 5 mmol) and EtOAc (2.0 mL, 20.0 mmol) in EtOH (100 mL) was added a solution of NaOEt in EtOH (13 mL, 50.0 mmol) and refluxed for 6 h. The reaction mixture was cooled and all the solvent was evaporated under reduced pressure. The residue was dissolved in water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried on Na2SO4 and concentrated to provide 1.0 g of tert-butyl (5-methyl-1,2,4-oxadiazol-3-yl)methylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[N:19]=[C:18]([S:25][CH3:26])[N:17]=3)=[CH:14][CH:15]=2)=[CH:9][C:8]([C:27]([F:30])([F:29])[F:28])=[C:7]([C:31]#[N:32])[C:6]1=[O:33].[OH2:39].[OH2:40].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].C1C=C(C([O-])=O)C(C(O[O-])=O)=CC=1.[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[N:19]=[C:18]([S:25]([CH3:26])(=[O:40])=[O:39])[N:17]=3)=[CH:14][CH:15]=2)=[CH:9][C:8]([C:27]([F:29])([F:30])[F:28])=[C:7]([C:31]#[N:32])[C:6]1=[O:33]
Reactant: CCOc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)nc(SC)n1
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CCOc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)nc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile (49 mg, 0.087 mmol) was dissolved in a mixture of dichloromethane (2 mL) and methanol (0.4 mL). To this solution was added magnesium monoperoxyphthalate hexahydrate, MMPP, (108 mg, 0.218 mmol, 80% tech.) and the mixture was stirred at ambient temperature for overnight. After this period the reaction mixture was combined with dichloromethene (20 mL) and was washed with 1M NaHCO3 (2×10 mL), and brine (10 mL). The resulting organic layer was separated and dried over anhydrous Na2SO4 and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (25-50% EtOAc/Hexane) to yield 1-(2,4-difluorobenzyl)-6-[5-(6-ethoxy-2-methanesulfonyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (42 mg, 80%) as a yellow solid. 1H-NMR (CDCl3): δ 7.72 (m, 1 H), 7.14 (m, 1 H), 7.13 (m, 1 H), 7.07 (s, 1 H), 6.88 (m, 1 H), 6.78 (m, 1 H), 6.63 (s, 1 H), 5.40 (s, 2 H), 4.61 (q, J=7.1 Hz, 2 H), 3.36 (s, 3 H), 1.46 (t, J=7.1 Hz, 3 H). MS(ES+): 597.2 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])CCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:11]1([CH2:13][C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: C=C(C(F)(F)F)[Sn](CCCC)(CCCC)CCCC
Reactant: C=C(C)CCCc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(CC1(C)CCCc2ccccc21)C(F)(F)F
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of 1-iodo-2-(4-methylpent-4-en-1-yl)benzene (Intermediate 2) (8.3 g, 29 mmol), triphenylphosphine (1.57 g, 6 mmol), cuprous iodide (0.572 g, 3 mmol) and palladium acetate (0.673 g, 3 mmol) in anhydrous N,N-dimethylformamide (200 ml) was added tributyl[1-(trifluoromethyl)ethenyl]stannane (Intermediate 3) (14.5 g, 37.7 mmol). The flask was evacuated and filled with nitrogen four times and then placed in a bath preheated to 110° C. and stirred for 3 h. The mixture was allowed to cool, the solution was decanted from the black solid and concentrated to low volume. Heptane (200 ml) and water (200 ml) were added, insoluble material was filtered off, and the layers were separated. The aqueous layer was re-extracted with heptane (100 ml) and the combined organic layers were washed successively with water (2×200 ml), aqueous lithium chloride solution (200 ml), water (200 ml) and saturated brine (200 ml), dried over anhydrous sodium sulphate and evaporated. The resulting oil was purified by flash chromatography on an 800 g Biotage silica cartridge eluted with heptane to give the title compound (5.28 g, 72%).
Reaction SMILES: Cl.[N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[NH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:2]2[C:6]3[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=3[N:4]=[CH:3]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
In dichloromethane (15 ml), methyl 5-benzimidazolecarboxylate hydrochloride (1.00 g) was suspended. To the resulting suspension, triethylamine (1.50 ml) and triphenylmethyl chloride (1.50 g) were added, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby title compound (2.10 g, quant.) was obtained as a yellow solid.
Reaction SMILES: N1C=CC(C2[N:19]3[N:10]([CH2:11][C:12]4[C:17]([CH2:18]3)=[CH:16][CH:15]=[CH:14][CH:13]=4)C(=O)C=2)=NC=1.COC(=O)C(C1C=CC(F)=CC=1)C(C1C=CN=C(SC)N=1)=O>>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][NH:19][NH:10]1
Reactant: O=c1cc(-c2ccncn2)n2n1Cc1ccccc1C2
Agent: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Product: c1ccc2c(c1)CNNC2

Procedure:
The following scheme illustrates the assembly of the 3-pyrimidin-4-yl-5,10-dihydro-pyrazolo[1,2-b]phthalazine-1-one scaffold by the convergent step which condenses intermediates 3 and 5. The resulting intermediate is then transformed into the final compound having the selected R unit.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:16](O)(=O)[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>C1(C)C(C)=CC=CC=1>[OH:18][CH:17]([C:16]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=2[N:1]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)c1ccc2oc(C(O)c3ccccc3)nc2c1
Reaction time: 24 h

Procedure:
A mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (1.2 g.), mandelic acid (1 g.) and xylene (50 ml.) was heated using a Dean and Stark apparatus. After 24 hours, the solution was evaporated to dryness and the residue was taken up in chloroform. This solution was washed first with sodium hydroxide solution, then with hydrochloric acid and finally dried over sodium carbonate. The solution was evaporated to dryness to give ethyl 2-[2-(α-hydroxybenzyl)-5-benzoxazolyl]propionate, the structure of which was confirmed by n.m.r. spectroscopy.
Reaction SMILES: [Br:1][C:2]1([Br:14])[CH2:4][C:3]1([Br:13])[CH2:5][CH2:6][O:7]C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CO.O>[Br:1][C:2]1([Br:14])[CH2:4][C:3]1([Br:13])[CH2:5][CH2:6][OH:7]
Reactant: CCOC(C)OCCC1(Br)CC1(Br)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCCC1(Br)CC1(Br)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a slurry of 16.5 g (0.0418 mol) of 1,1,2-tribromo-2-[2-(1-ethoxy-ethoxy)-ethyl]-cyclopropane in 145 ml methanol and 40 ml water, was added 0.306 g (0.00161 mol) p-toluene sulfonic acid monohydrate and 145 ml 6M hydrochloric acid. After stirring at room temperature for 1 hour, the solvent was removed from the reaction mixture in vacuo. To the residue, there was added ethyl acetate and water. The resulting mixture was transferred to a separatory funnel and the phases were separated. The isolated organic layer was washed with brine then dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 11.9 g of 1,1,2-tribromo-2-(2-hydroxyethyl)cyclopropane as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].CCN(C(C)C)C(C)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.CCOC(C)=O>[CH3:18][S:19]([O:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5])(=[O:21])=[O:20]
Reactant: CC(=O)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)C(C)(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a solution of 4-hydroxy-3,3-dimethylbutan-2-one (9.7 g, 84 mmol) and DIPEA (16.04 mL, 92 mmol) in DCM (50 mL) cooled to 0° C. was dropwise added methanesulfonyl chloride (7.16 mL, 92 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3, sat. NaCl, dried (MgSO4), filtered and concentrated to yield 2,2-dimethyl-3-oxobutyl methanesulfonate (14.6 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.21 (2H, s), 3.04 (3H, s), 2.21 (3H, s), 1.25 (6H, s).
Reaction SMILES: P(O[CH2:10][CH3:11])(OCC)(OCC)=O.Br[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C@H:20]2[CH2:25][CH2:24][Si@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1>C1COCC1.[Cu]I>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:10][CH2:11][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C@H:20]3[CH2:25][CH2:24][Si@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CBr)CC2)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(CC)cc3)CC2)CC1

Procedure:
22.7 g (0.1 mol) of 4-(3-bromopropyl)-1-ethylbenzene was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was further dropped in a solution, in 500 ml of THF, of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 31.7 g (0.1 mol) of trans-4-(trans-4-bromomethylcyclohexyl)-1-propyl-1-silacyclohexane. The resultant product was subjected to ordinary aftertreatments to obtain trans-4-(trans-4-(4-(4-ethylphenyl)butyl)cyclohexyl)-1-propyl-1-silacyclohexane. After ordinary aftertreatments, the product was purified through chromatography to obtain 31.7 g (yield: 82%) of the trans isomer product.
Reaction SMILES: Cl.[OH:2][C:3]1([C:7]([OH:9])=[O:8])[CH2:6][NH:5][CH2:4]1.[CH2:10]=O>O.O.[Pt]=O>[CH3:10][N:5]1[CH2:6][C:3]([OH:2])([C:7]([OH:9])=[O:8])[CH2:4]1
Reactant: O=C(O)C1(O)CNC1
Reactant: C=O
Agent: O=[Pt]
Agent: Cl
Solvent: O
Product: CN1CC(O)(C(=O)O)C1
Reaction time: 46 h
Yield: 74.9 %

Procedure:
To a solution of 500 mg (3.26 mmoles) of 3-hydroxyazetidine-3-carboxylic acid hydrochloride in 15 ml of water are added 1.06 ml of 37% formalin and 250 mg of platinum oxide monohydrate, and the mixture is kept at ambient temperature under atmospheric pressure for 46 hours. The catalyst is filtered off and washed with water. The combined filtrate and washings are evaporated under reduced pressure. The residue (0.79 g) is dissolved in 10 ml of water, adsorbed on 30 ml of Amberlite IR-120 B (H+), and eluted with 100 ml of 2 N aqueous ammonium hydroxide solution. The eluate is evaporated under reduced pressure. The residue (431 mg) is crystallized from water-acetone to yield 1-methyl-3-hydroxyazetidine-3-carboxylic acid as prisms.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[CH2:8]1)=[O:19])([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1ccc2c(c1)CCNC2
Product: Cc1ccc2c(c1)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6-methyl-1,2,3,4-tetrahydro-isoquinoline (CA [42923-76-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([F:2])[CH:8]=1)=[S:21]
Reactant: NCc1ccnc(F)c1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: Cl
Product: Fc1cc(CNC(=S)Nc2cccc(Cl)c2Cl)ccn1
Yield: 53 %

Procedure:
Prepared in 53% yield from the product of Example 143A and 2,3-dichlorophenylisothiocyanate according to the procedure described for Example 141B. MS (ESI+) m/z 329.9 (M+H)+; 1H NMR (DMSO-d6) δ 4.79 (d, J=5.8 Hz, 2H), 7.02 (br s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.48-7.61 (m, 2H), 8.18 (d, J=5.1 Hz, 1H), 8.43 (br s, 1H), 9.69 (br s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])[N:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:24])([Cl:23])[S:21]Cl>C1C=CC=CC=1>[CH3:1][N:2]([S:21][C:20]([Cl:24])([Cl:23])[Cl:19])[C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:9])[Cl:10])[N:4]=1
Reactant: CNc1nc(C(Cl)(Cl)Cl)ns1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(SC(Cl)(Cl)Cl)c1nc(C(Cl)(Cl)Cl)ns1
Yield: 23 %

Procedure:
To a 3-neck flask equpped with condenser, thermometer and stirring bar was added 11.6 g (0.05 mole) 5-methylamino-3-trichloromethyl-1,2,4- thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 20 hours and filtered hot. The filtrate was evaporated under vacuum to give a beige solid which was refluxed in 400 milliliters of ligroin and filtered. The ligroin was cooled, filtered and the filtrate evaporated to 20 milliliters and filtered. The resulting solid was recrystallized again from ligroin to obtain 4.4 g (23% yield) of product; mp=106° C.