Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:18][O:17][B:16]([OH:19])[C:15]=2[CH:20]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Cl:27]C1C=C(C=CC=1F)C#N.CCOC(C)=O>CS(C)=O>[Cl:27][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:18][O:17][B:16]([OH:19])[C:15]=2[CH:20]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(Cl)c1
Temperature: 90 °C
Yield: 33.3 %

Procedure:
To a solution of 3H-benzo[c][1,2]oxaborole-1,6-diol (5) (300 mg, 2 mmol) in DMSO (30 mL) were added K2CO3 (828 mg, 6 mmol) and 3-chloro-4-fluoro-benzonitrile (933 mg, 6 mmol). The reaction was heated at 90° C. for 7 hours. After the cooling of reaction solution, EtOAc (50 mL) was added. The organic layer was washed with water (5×50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-benzonitrile (6) 190 mg in 33.3% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1 H), 8.22 (s, 1 H), 7.77 (d, J=7.81 Hz, 1 H), 7.50 (d, J=8.20 Hz, 1 H), 7.34 (s, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.01 (d, J=8.59 Hz, 1 H), 4.99 (s, 2 H). ESMS (m/z): 284 (M−H)−. HPLC: 96.41% (220 nm), 96.0% (maxplot).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:16][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[N:5]=[C:4]([C:12]([F:14])([F:15])[F:13])[N:3]=[C:2]([Cl:1])[C:11]1=2
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2Br
Yield: 58.3 %

Procedure:
To a solution of 17.63 g of 4-chloro-5,6,7,8,-tetrahydro-2-trifluoromethylquinazoline in 220 mL of chloroform was added 14.6 g of N-bromosuccinimide and 0.85 g of AIBN. The resulting reaction mixture was heated to reflux overnight under a nitrogen atmosphere. The reaction was cooled, filtered and all solvents were removed by evaporation. The residue was purified on a silica column (5% ethyl acetate in hexane) to yield 13.7 g (58%) of the required compound. This material was carried to the next step with no further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:10][O:8][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnccn1
Reaction time: 72 h
Yield: 7.7 %

Procedure:
To pyrazine-2-carboxylic acid (15.0 g, 121 mmol) in DMF (150 mL) were added K2CO3 (50 g, 363 mmol) and MeI (9.0 mL, 145 mmol). After stirring for 3 days, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (1.28 g, 8%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[CH3:9][C:10]1([CH3:30])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:11]1>CC(C)=O>[CH3:7][N:11]1[C:10]([CH3:30])([CH3:9])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CC1(C)Cc2ccccc2C(c2cnc3ccccc3c2)N1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1C(c2cnc3ccccc3c2)c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
Potassium carbonate (500 mg, 3.6 mmol) and methyl iodide (0.33 mL, 5.0 mmol) were added to an acetone (2 mL) solution of 3-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl) quinoline (144 mg, 0.5 mmol) followed by stirring for 3 hours at room temperature, filtering, concentrating the filtrate and applying the resulting residue to chromatography to obtain 60 mg of the target compound (yield: 40%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To 1-(t-butyloxycarbonyl),4-(5-cyano,2-pyridinyloxy)piperidine (1.6 g) in dichloromethane (20 mL) was added trifluoroacetic acid (1.2 mL) and the reaction stirred at room temperature for 1 hour. The reaction was quenched by evaporation of trifluoroacetic acid dissolving the residue in water, basifying with sodium hydrogen carbonate and extracting the dichloromethane. The organic layer was then washed with water, brine, dried (MgSO4) and evaporated to yield 4-(5-cyano,2-pyridyloxy)piperidine as a white crystalline solid (337 mg), MS: m/z 279 (MH+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:23]1[S:27][C:26]2=[N:28][C:29]([C:31]([OH:33])=[O:32])=[CH:30][N:25]2[CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:34]([O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:16]([C:23]1[S:27][C:26]2=[N:28][C:29]([C:31]([O:33][C:46]3[CH:47]=[CH:48][C:43]([O:42][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:44][CH:45]=3)=[O:32])=[CH:30][N:25]2[CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCc1cn2cc(C(=O)O)nc2s1
Reactant: CCCCCCCCOc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(OC(=O)c2cn3cc(CCCCCCC)sc3n2)cc1

Procedure:
1.2 g of N,N'-dicyclohexylcarbodiimide are added in portions to a solution of 1.3 g of 2-heptylimidazo[2,1-b]-thiazole-6-carboxylic acid, 1 g of 4-octyloxyphenol and 0.1 g of 4-(dimethylamino)pyridine in 25 ml of dichloromethane within 10 minutes while stirring. The mixture is stirred overnight at room temperature and then filtered. The filtrate is diluted with dichloromethane, washed with two portions of 50 ml each of saturated sodium carbonate solution and then with water, dried over magnesium sulphate and filtered, and the filtrate is evaporated. Recrystallization of the residue from ethyl acetate/cyclohexane gives 4-octyloxyphenyl 2-heptylimidazo[2,1-b]thiazole-6-carboxylate, m.p.(C/SA): 112.6° C., c.p.(SA /I): 151.4° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](=[O:23])=[O:22].Cl>O1CCCC1>[CH3:6][O:7][C:8]1[C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: COc1ccccc1NC(=O)C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
n-Butyllithium (1.6M solution in hexane; 200 ml, 0.32 mol) was added dropwise under nitrogen at −10° C. to a stirred solution of N-(2-methoxyphenyl)pivalamide (27.6 g, 0.133 mol) in tetrahydrofuran (600 ml), the mixture was allowed to warm to ambient temperature, stirred for a further 2 hours, then it was added to a large excess of crushed solid carbon dioxide. The mixture was allowed to warm to ambient temperature, 3M hydrochloric acid (200 ml) was added and the tetrahydrofuran was removed in vacuo. The resulting solid was collected by filtration and crystallised from acetonitrile to give 3-methoxy-2-pivalamidobenzoic acid (21 g; 63%) as a solid, m.pt. 117-120° C. Concentration of the liquor yielded a second crop (2.6 g; 8%).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]2=[O:15])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>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>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][N:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]3=[O:15])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1cccn(Cc2ccc(Br)cc2)c1=O
Reactant: OB(O)c1ccncc1
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+]
Product: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=O
Yield: 81.7 %

Procedure:
Reaction of 145 (0.25 g, 0.85 mmol), pyrdin-4-ylboronic acid (0.12 g, 1.02 mmol), 2M aq. K2CO3 (0.23 g, 1.69 mmol), Pd(PPh3)4 (2.5 mol %) according to method described for synthesis of 146a within 18 h afforded 203 mg of 146i (82%) of white solid. 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J=4.5, 1.6 Hz, 2H), 7.48 (m, 2H), 7.36 (m, 4H), 6.87 (dd, J=6.9, 1.7 Hz, 1H), 6.53 (dd, J=7.4, 1.6 Hz, 1H), 6.03 (t, J=7.2 Hz, 1H), 5.13 (s, 2H), 3.72 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.82, 150.32, 150.01, 149.90, 147.40, 137.31, 137.28, 128.57, 127.68, 127.04, 121.22, 111.90, 104.98, 55.57, 51.42. HRMS (EI) calcd for C18H16N2O2 [M]+ 292.1212. found 292.1205.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9])[CH3:15]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CC(C)(C)CC1=O
Yield: 46 %

Procedure:
According to Scheme 2 Step 1: A solution of 5,5-dimethylcyclohexane-1,3-dione (428 mmol, 60 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (514 mmol, 68.2 mL) was stirred at room temperature for 1 hour. After evaporation and trituration in cyclohexane, 38.5 g (197 mmol, 46%) of 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione were obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Product: CCCCOC(=O)c1nc(-c2cccnc2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 3-(tributylstannyl)pyridine: MS (m/z) 344.2 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[Li].Cl[CH2:18][O:19][CH2:20][CH2:21][Cl:22]>O1CCCC1>[Cl:22][CH2:21][CH2:20][O:19][CH2:18][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1CCOCC1
Reactant: ClCCOCCl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(COCCCl)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of tetrahydro-2H-pyran-4-carbonitrile (3.80 g, 34.2 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min to a cold (−78° C.) solution of lithium diisopropylamine (37.5 mmol) in tetrahydrofuran (50 ml). After 30 min, a solution of 2-chloroethyl chloromethyl ether (5.00 g, 38.7 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min and the mixture stirred for 30 min. The cooling bath was then removed and the solution was allowed to warm up to 25° C. then stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic fraction was dried over anhydrous magnesium sulfate and concentrated. Filtration of the residue on silica gel (elution toluene-ethyl acetate 8:2) followed by distillation in vacuo gave 6.33 g (91% yield) of the title nitrile as a clear oil: bp 90-100° C./0.2 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.74 (2H, m, CH2), 1.92 (2H, m, CH2), 3.58 (2H, s, CH2), 3.67 (2H, t, J=5.6 Hz, CH2), 3.74 (2H, dt, J=2.3 Hz and J=12.4 Hz, CH2), 3.83 (2H, t, J=5.6 Hz, CH2), 4.0 (2H, m, OCH2).
Reaction SMILES: C([O-])(=O)C.[K+].[CH3:6][S:7]([NH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH2:17][C:18]([O:20]CC)=[O:19])=O)=[CH:13][CH:12]=1)(=[O:9])=[O:8].Cl.[NH2:26]O.CO>O>[CH3:6][S:7]([NH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]2[CH2:17][C:18](=[O:19])[O:20][N:26]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C2=NOC(=O)C2)cc1
Yield: 55.1 %

Procedure:
Potassium acetate (8.2 g) was added to a mixture of ethyl 4-methanesulfonamidobenzoylacetate (23.0 g), hydroxylamine hydrochloride (5.8 g) and methanol (35 ml), and the mixture was heated for refluxing for 30 minutes. The reaction mixture was poured into water (210 ml) to filter off the deposited crystals and dry them, whereby 3-(4-methanesulfonamidophenyl)isoxazoline-5-one (11.3 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CO>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 205.5 %

Procedure:
A cooled (0° C.) solution of 30A (15.0 g, 64.8 mmol) and imidazole (22.0 g, 324 mmol) in dry DMF (110 ml) was treated with tert-butyldimethylsilyl chloride (24.3 g, 162 mmol), warmed to RT and stirred for 24 h. The reaction mixture was treated with methanol (150 ml), stirred at RT for another 24 h then partitioned between 10% aqueous citric acid (225 ml) and EtOAc (3×1.0 L). The extracts were washed with brine (200 ml), dried (Na2SO4) and filtered. The filtrate was concentrated to dryness to give a thick colorless syrup (46.0 g). Purification of a portion (20 g) by using automated flash chromatography (135 g silica gel column, EtOAc/hexane gradient) gave the title compound as a thick clear syrup (9.7 g, 99.7%).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][N:8]([CH3:12])[CH2:7][CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Cc1cc2c(o1)CCN(C)CC2O
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(o1)CCN(C)CC2Oc1ccc(Cl)c(Cl)c1

Procedure:
The same method as in Example 1 was conducted using 2,6-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepin-4-ol (Reference Example 26) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[N:30]#[C:31][NH2:32]>>[F:26][C:25]([F:28])([F:27])[O:24][C:20]1[CH:19]=[C:18]([C:15]2[C:14]3[CH:29]=[C:10]([C:7]4[O:6][C:5]([NH:32][C:31]#[N:30])=[N:9][N:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Product: N#CNc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 24 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using cyanamide instead of 3-fluorobenzylalcohol, the title compound (yield 24%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(C)c2c1
Reaction time: 1 h

Procedure:
A mixture of methyl-indole-6-caroxylate (3.0 g, 16.6 mmol), sodium hydride (1.0 g, 24.9 mmol), DMF (20 ml) was stirred for 1 h at room-temperature followed by addition of iodomethane (4.7 g, 33.2 mmol) and stirring at room-temperature for 15 h. The mixture was extracted with chloroform and evaporated. The product was isolated by evaporation. Yield 3.2 g (100%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]=[C:12]2[CH2:25][C:26]([NH2:28])=[O:27])C.[OH-].[Na+].Cl>CCO.C1COCC1>[NH2:28][C:26](=[O:27])[CH2:25][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)Cc1cn(Cc2ccccc2)c2ccc(OCCCC(=O)O)cc12
Yield: 45.5 %

Procedure:
4-[[3-(2-Amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (260 mg, 0.66 mmol) was stirred with 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF for 18 hours. The mixture was acidified with 5N HCl, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution and dried (Na2SO4). After concentrating, the residue was crystallized from methylene chloride/ethanol to give 110 mg (46% yield) of 4-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 160-163° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13]C(C)([O-])C.[K+].IC>C1COCC1>[CH3:13][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCCC1=O
Reaction time: 0.08 h

Procedure:
For the synthesis of the protected acid side-chain 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid, ethyl 2-oxocyclohexane carboxylate (8.5 g, 50 mmol) was dissolved in dry THF at ambient temperature under N2. Potassium tert-butoxide (75 mmol) was added slowly and the reaction was stirred for 5 minutes. Iodomethane (100 mmol) was then added and the reaction was stirred at ambient temperature for 1 hour. The reaction solvent was removed under reduced pressure and the residue was partitioned between water and hexane. The organic layer was dried over sodium sulfate and reduced under reduced pressure to give racemic ethyl 1-methyl-2-oxo-cyclohexanecarboxylate as a colourless oil (8.11 g 88%); δH (400 MHz, CDCl3) 4.25-4.12 (2H, m, OCH2CH3), 2.55-2.40 (3H, m, CH2CO and one other cyclohexane peak), 2.05-1.95 (1H, m, cyclohexane), 1.77-1.57 (3H, m, cyclohexane), 1.50-1.40 (1H, m, cyclohexane), 1.28 (3H, s, CCH3) and 1.25 (1H, t, J 7, CH2CH3). Ethyl 1-methyl-2-oxo-cyclohexanecarboxylate (5.52 g, 30 mmol) was dissolved in ethanol (100 ml) at ambient temperature and sodium borohydride (1.14 g, 30 mmol) was added slowly. After 1 hour the reaction solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic extracts were dried over sodium sulphate and reduced to give ethyl 2-hydroxy-1-methylcyclohexanecarboxylate as a mixture of diastereoisomers (5.37 g 96%). This material was then protected and the ester hydrolysed as follows: Ethyl 2-hydroxy-1-methylcyclohexanecarboxylate (16.7 mmol) was dissolved in dichloromethane along with 3,4-dihydro-2H-pyran (17 mmol) and para-toluene-sulphonic acid (5 mg), and the reaction was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to give a residue to which was added ethanol (40 ml), water (10 ml) and potassium hydroxide (20 mmol). The mixture was heated at reflux overnight and allowed to cool. The reaction solvent was removed under reduced pressure and the residue was partioned between water and diethyl ether. The aqueous layer was acidified to pH 2 and then extracted with diethyl ether. This ether layer was dried over sodium sulphate and reduced in vacuo to give crude 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid (2.52 g) as a mixture of diastereoisomers. This material was used in the synthesis of (S)-3-(2′-hydroxy-1′-methylcyclohexanecarbonyl)amino-caprolactam above
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:32]=[CH:31][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36]/[N:35]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:31][CH:32]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, 3-{4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoylamino}-propionic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=460.3 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cnn(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carbaldehyde (2.59 g), sodium hydride (60% in oil, 1.13 g), ethyl diethylphosphonoacetate (5.8 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate (2.72 g, 64%) as crystals from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 43-44° C.