Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.FC(F)(F)S(O[Si:20]([CH3:23])([CH3:22])[CH3:21])(=O)=O.CCOCC>ClCCl>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:6][C:2](=[CH:3][CH2:4][CH3:5])[CH3:1]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCC=C(C)O[Si](C)(C)C
Yield: 25.7 %

Procedure:
In 500 mL of dichloromethane, was dissolved 22.0 mL (207 mmol) of 2-pentanone. While stirring the resulting solution in an ice bath, 44 mL (317 mmol) of triethylamine was added to the solution, and then, 42 mL (232 mmol) of trimethylsilyl trifluoromethanesulfonate was added dropwise to the solution. After the addition of trimethylsilyl trifluoromethanesulfonate, the mixture was stirred for 1 hour at room temperature, poured into ether (500 mL)/a saturated aqueous sodium hydrogencarbonate solution (300 mL) so as to extract the ether layer. The ether layer was washed with saturated sodium chloride water and water, dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled under normal pressure to collect fractions of 110 to 125° C. As a result, 8.43 g (53.2 mmol, 49.4%) of 2-trimethylsilyloxy-2-pentene was obtained. According to a similar method, 5.33 g (33.6 mmol, 32.3%) of 2-trimethylsilyloxy-2-pentene was obtained from 11.0 mL (103.8 mmol) of 2-pentanone.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: ClCCCCCCc1ccncc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCc1ccncc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
NaCN (509 mg) in DMSO (4.25 ml) is added to 4-(6-chlorohexyl)pyridine (1.71 g) dissolved in DMSO (4.25 ml). The mixture is stirred at 60° C. for 3 hours, poured into water (100 ml) and extracted with chloroform (3×15 ml). The combined extracts are washed with water (2×20 ml), dried (Na2SO4) and the solvent evaporated to give 4-(6-cyanohexyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([OH:10])=O.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Na].Cl>C(O)C.O>[C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[OH:10])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NC1=C(C(=O)O)CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Reaction time: 30 h

Procedure:
A mixture of a 60:40 mixture of the ethyl and methyl esters of 2-amino cyclohex-1-ene carboxylic acid (47.2g; 0.29 mole) and diethyl malonate (46,4g; 0.29 mole) were added to a solution of sodium (7.2g; 0.29 mole) in ethanol (145 ml) stirred at ca 110° C for 30 hrs. in an autoclave. The product was acidified with 5N HCl to pH 4.0 and diluted with water. The precipitated ester was filtered off and recrystallised from ethanol with charcoalisation, m.p. 236° - 7°(d).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12](OCC)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][N:10]=1
Reactant: CCOC(=O)C1=NOC(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1=NOC(c2ccccc2)C1
Reaction time: 4 h

Procedure:
To a solution of 7 g of ethyl 5-phenyl-4,5-dihydroisoxazol-3-ylcarboxylate in 70 ml of methanol, cooled with ice, is added 1.5 g of sodium borohydride in small portions with stirring. After 4 hours has passed, the solvent is distilled off under reduced pressure and the residue is extracted with ethyl acetate. The extract is washed with water, dried and the solvent is evaporated. The crystalline residue thus obtained is recrystallized from isopropyl ether, giving 3-hydroxymethyl-5-phenyl-4,5-dihydroisoxazole in the form of white crystals. Melting point: 73°-74° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>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.O>[OH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Oc1ccccc1-c1ccccn1
Yield: 80.1 %

Procedure:
9.5 g (˜43 mmol) of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 6.8 g (˜43 mmol) of 2-bromopyridine, 1.5 g (1.3 mmol) of Pd(PPh3)4, and 16 g (116 mmol) of K2CO3 were added to a 250 mL round bottle flask, along with a solvent mixture of 120 mL of dimethoxyethane and 150 mL of water. The mixture was heated to reflux for 24 hours under nitrogen. The reaction mixture was extracted with ethyl acetate and the organic phase was separated on silica gel column with 15% ethyl acetate as elute solvent. ˜5.9 g (yield ˜80%) of 2-(2-hydroxyphenyl)pyridine was obtained as a colorless liquid.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=O.C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: COc1ccc(C(=CC#N)c2ccncc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 4-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude product was slurried in 10 mL of hexane. The mixture was filtered, the solid was washed with hexane, air dried and then dried in vacuo to afford 0.91 g (85%) of a mixture of the E and Z isomers as an off white solid: mp 116-125° C.; 1H NMR (CDCl3) δ8.80-8.63 (m, 4 H), 7.40-7.20 (m, 4 H), 7.04-6.74 (m, 6 H), 5.81 (s, 1 H), 5.70 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3) δ160.1, 157.0, 151.6, 151.1, 150.3, 149.2, 148.9, 146.7, 144.9, 129.6, 127.8, 123.7, 123.1, 122.7, 122.1, 117.4, 117.1, 112.3, 111.0, 110.5, 96.1, 94.8, 56.0, 56.0; Anal. Calcd for C16H14N2O2. Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.35; H, 5.43; N, 10.47.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Cl.[CH3:16][CH:17]1[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1>>[CH3:16][CH:17]1[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CC1CCN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Product: CC1CCn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture of 7.76 g (40.0 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582), 6.0 g (40.0 mmol) 6-methyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][O:42][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Fc1ccc(OCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
A mixture of 4 fluorophenol (6.01 g, 54 mmol), triphenylphosphine (6.87 g, 64 mmol), and 1-benzyl-4-hydroxymethylpiperidine (11.0 g, 54 mmol) in benzene (300 mL) was stirred at 10°-15° C. Diethyl azodicarboxylate (11.2 g, 10.1 mL, 64 mmol) was added dropwise. The reaction mixture was heated to reflux temperature and stirred for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; the organic solution was washed with water three times, a 2N sodium hydroxide solution three times, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give crude product. Column chromatography (ethyl acetate:hexanes::1:1) gave, after removal of solvent, a pale yellow oil (3.88 g, 24% yield): 7.40-7.25 (m, 5H), 7.0-6.7 (m, 4H), 3.75 (d, 2H, J=4), 3.50 (s, 2H), 2.9 (br d, 2H, J=4), 2.1-1.25 (m, 7H); IR (neat): 3084(m), 3062(m), 2921(s), 2802(s), 2758(s), 1601(m), 1505(s), 1467(s), 1454(s), 1394(s); HR-MS: Calcd. for C19H22FNO: 299.1684; Found: 299.1685.
Reaction SMILES: [C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)=[C:9](I)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[S:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>[Hg]>[C:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)=[C:9]([C:36]2[S:35][CH:39]=[CH:38][CH:37]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc(I)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Reactant: c1ccsc1
Agent: [Hg]
Product: CC(C)C(=O)Nc1nc(-c2cccs2)c2ncn([C@H]3C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O3)c2n1
Yield: 78 %

Procedure:
The compound (18) 294 mg (0.5 mmol) obtained in the above (A) was dissolved in thiophene 80 ml under argon atmosphere and the solution was transferred into the photochemical reaction vessel (Pyrex). Ultraviolet ray was irradiated using 400 W mercury lamp for 24 hours under argon atmosphere. The reaction mixture after irradiation was concentrated, and the residue was purified using short column (developer: isopropanol:dichloromethane=3:197) to obtain the product (19) 212 mg (0.39 mmol) (78.0%).
Reaction SMILES: [CH2:1]1[C@@H:6]([OH:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].O>CO>[CH2:1]1[C:2]([OH:10])([C:11]([OH:13])=[O:12])[CH2:3][C@@H:4]([OH:9])[CH:5]([OH:8])[C@@H:6]1[OH:7]
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Solvent: O
Solvent: CO
Product: O=C(O)C1(O)C[C@@H](O)C(O)[C@H](O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Fifteen grams of the hydrochloride salt is neutralized to the free base form as described in Synthesis Example 1. The free base (11.12 g, 0.025 mol) is isolated and dissolved in approximately 200 ml of methanol. Quinic acid (4.91 g, 0.025 mol) is dissolved in 200 ml of a hot solution consisting of 90% methanol and 10% water and added to the solution containing free base. The mixture is stirred for 2 hours at a temperature up to 100° C. The solvent is evaporated under reduced pressure and the resultant solid is collected, dried, and recrystallized from ethanol. The quinate salt obtained (12.4 g, 0.19 mol, 76%) melted with a three degree range between the limits of 136°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][N:13]2[C:12](=[O:24])[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:14]2)[CH2:29][CH2:28]1
Reactant: ClCC1CC1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2nn(CC3CC3)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 93.8 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 93.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([C:36]([CH3:40])([CH3:39])[CH2:37]O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[K+].[Br-].Cl>>[CH:30]1([C:36]([CH3:40])([CH3:39])[CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:37][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)([CH3:40])[CH3:39])=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)(CO)C1CCCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)C1CCCCC1)(C(=O)OCC(C)(C)C1CCCCC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo-[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexyl-2-methylpropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.1 (s, 6H, CH3, CH3), 1.45 (s, 6H, CH3, CH3), 1.5 (s, 6H, CH3, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 698 (M+H)+ ; Analysis for: C40H56ClNO7 ×HCl: Calc'd: C, 65.38; H, 7.82; N, 1.91; Found: C, 65.32; H, 7.96; N, 1.94.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15]C)=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1CCN(C(=O)OC)C(C2CCCCC2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1C1CCCCC1
Yield: 70.4 %

Procedure:
Dimethyl 2-cyclohexylpiperidine-1,4-dicarboxylate (4.90 g, crude) was dissolved in acetonitrile (30 mL) and water (0.600 mL). lithium bromide (9.28 g, 106.80 mmol) and triethylamine (7.40 mL, 53.40 mmol) were added and the mixture was heated under reflux for 2 h. Water (60 mL) and MTBE were added. The organic phase was extracted with water (×2). MTBE was added to the pooled aqueous layer and the solution was acidified to pH 1 with 2 M HCl and then extracted with MTBE (×2). The combined organic layer was dried over Na2SO4 and evaporated to give 2-cyclohexyl-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.28 g, 91% (over 2 steps)) as a slightly yellow semisolid. MS m/z 270 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([OH:33])[CH2:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: OC1(c2ccc(Br)cc2)CCC1
Product: O=C1N(c2ccc(C3(O)CCC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 1-(4-bromo-phenyl)-cyclobutanol (prepared as described in SYNLETT 2004, No. 8, pp 1440-1442). White solid. MS (ESI): 475.0 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:12]([CH2:26][C:27]([OH:29])=[O:28])[S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:12]([CH2:26][C:27]([OH:29])=[O:28])[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:11][CH2:10][CH2:9]2)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(O)CN(C1(c2ccc(Br)cc2)CCC1)S(=O)(=O)c1ccc(OC(F)F)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: O=C(O)CN(C1(c2ccc(-c3cncnc3)cc2)CCC1)S(=O)(=O)c1ccc(OC(F)F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of 2-(N-(1-(4-bromophenyl)cyclobutyl)-4-(difluoromethoxy)phenylsulfonamido) acetic acid (20 mg, 0.041 mmol) in n-butanol (2 mL) was added pyrimidin-5-ylboronic acid (7.58 mg, 0.061 mmol), followed by potassium phosphate (17.32 mg, 0.082 mmol) and Pd2 dba3 (2.345 mg, 4.08 μmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (3.89 mg, 8.16 μmol). The mixture was degassed and flushed with argon and then shook at 100° C. for 3 h. The resultant mixture was filtered and the filtrate purified using Shimadzu prep HPLC employing an ACN/water and 0.1% TFA buffer with a Xterra column, 30 mm×100 mm, Gradient over 15 min; Starting conc: 10% B; Ending conc: 100% B. The solvent was removed in vacuo to give 3.3 mg (16% yield, 95% pure) of the title compound as a light gray solid. ESI-MS m/z 490 (MH+), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.67 (q, J=10.07 Hz, 1H), 1.78-1.92 (m, 1H), 2.63 (t, J=8.70 Hz, 2H), 2.86 (d, J=2.44 Hz, 2H), 4.21 (s, 3H), 6.58 (t, J=75.00 Hz, 1H), 7.09 (d, J=8.55 Hz, 2H), 7.54 (d, J=8.24 Hz, 2H), 7.67 (dd, J=14.80, 8.70 Hz, 4H), 9.10 (s, 2H), 9.31 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:31]=[CH:30][CH:29]=[CH:28][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([CH:26]=[CH2:27])=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1>CO.[Pd]>[CH2:26]([C:23]1[N:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[C:12]4[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=24)[N:10]=[CH:9][N:8]([C@H:7]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[OH:1])[C:17]3=[O:18])=[CH:25][CH:24]=1)[CH3:27]
Reactant: C=Cc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 15 h

Procedure:
To a solution of 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-vinylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one (0.040 g, 0.097 mmol) in 2 mL of methanol was added palladium on carbon (8.0 mg, 0.075 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 15 h and was then filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1960 for [M+H]+ [Calc'd for C25H26N3O3, [M+H]+=416.1969]: 1H NMR (400 MHz, CDCl3 δ 8.82 (d, J=7.9 Hz, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.60-7.52 (m, 3H), 7.37 (d, J=7.7 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.29-4.25 (m, 3H), 4.23 (s, 2H), 4.06-3.99 (m, 1H), 3.55 (t, J=11.2 Hz, 1H), 3.38-3.31 (m, 1H), 2.83 (q, J=7.4 Hz, 2H), 2.26-2.19 (m, 1H), 1.97-1.94 (m, 1H), 1.24 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C@H:4]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]1.[H-].[Na+].[C:23]1([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:1]/[N:2]=[CH:3]/[C@H:4]2[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R,5S)-(E)-4-hydroxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (100 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (14 mg 60% in oil) at 5° C. After being stirred at the same temperature for 30 minutes, to the solution was added diphenylmethyl bromide (86.6 mg) and the mixture was stirred in an ice bath for additional 2 hours. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and the crude residue was purified with preparative TLC with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give (2R,4R,5S)-(E)-4-diphenylmethoxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane