Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:3]=1[CH2:19][OH:20].[OH-].[K+].I[CH2:24][CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3]([CH2:19][O:20][CH2:24][CH3:25])=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCI
Reactant: COc1cc(Br)c(CO)cc1OCOCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOCc1cc(OCOCC[Si](C)(C)C)c(OC)cc1Br
Reaction time: 16 h
Yield: 92 %

Procedure:
The crude benzyl alcohol was stirred with a solution of potassium hydroxide (800 mg, 14.4 mmol) in DMSO (8 mL). Iodoethane (580 mL, 7.2 mmol) was added, and the reaction stirred for 16 h before it was diluted with H2O (30 mL) and extracted with ether (2×30 mL). Organics were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.30 g (92%) of the title compound as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 3.58 (q, 2H, J=6.9 Hz), 1.26 (t, 3H, J=6.9 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH:8]1([S:14][S:7][C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1occc1S
Reactant: SC1CCCCC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1occc1SSC1CCCCC1
Reaction time: 0.17 h

Procedure:
0.57 Grams (0.0050 moles) of 2-methyl-3-furanthiol and 1.16 grams (0.01 moles) of cyclohexylmercaptan are dissolved in 12 ml of diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added to the reaction mass. Over a period of 10 minutes, a solution of 1.9 grams (0.0075 moles) of iodine dissolved in 6 ml diethyl ether is added to the reaction mass with stirring until the iodine color remains. The reaction mass is then stirred over a period of 45 minutes.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][CH:14]=[C:15]([C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].CS(O[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([N:27]2[C:23]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11]3[N:21]([CH:22]=[C:9]([C:8]5[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:10]=3)[CH2:20][CH2:19][O:18]4)=[CH:24][CH:25]=[N:26]2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccn[nH]3)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 100 °C
Reaction time: 60 h
Yield: 6.6 %

Procedure:
A mixture of 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-(1H-pyrazol-5-yl)-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.00 g, 2.77 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.95 g, 6.92 mmol), and K2CO3 (1.90 g, 13.8 mmol) in CH3CN (50.0 mL) was stirred at 100° C. for 60 hr. After removal of the solvents, the residue was treated with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated to afford the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient CH3CN in 0.5% NH4HCO3 and followed by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 7% yield) as pale yellow solid. LCMS (ESI) m/z: 545.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 8.54 (d, J=10.5 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.26, (dd, J=2.5 Hz, 10.5 Hz, 1H), 7.12 (s, 1H), 6.40 (s, 1H), 5.94-5.91 (m, 1H), 4.59-4.56 (m, 4H), 4.42 (s, 1H), 4.02-3.99 (m, 2H), 2.84-2.83 (m, 2H), 1.92-1.85 (m, 4H), 1.50 (s, 6H), 1.40 (s, 9H).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:39][CH:38]=1)[NH2:35].[CH3:53][O:54][C:55]1[CH:59]=[C:58]([C:60](O)=[O:61])[O:57][N:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:41][CH:42]=1)[NH:35][C:60]([C:58]1[O:57][N:56]=[C:55]([O:54][CH3:53])[CH:59]=1)=[O:61]
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: COc1cc(C(=O)O)on1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCc2oc(=O)oc2C)on1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.7 %

Procedure:
EDCI (169 mg, 880 μmol) and HOBT (119 mg, 880 μmol) were added to a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (200 mg, 440 μmol) and 3-methoxyisoxazole-5-carboxylic acid (63 mg, 440 μmol) in DMF (10 mL). DIPEA (114 mg, 880 μmol) was added and the mixture was stirred for 5 hours at room temperature. The mixture was washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc=1:1) to yield the title compound as a white solid (60 mg). LC-MS: 576.1 [M+H]+. 1H-NMR: (DMSO-d6) 2.14 (s, 3H), 3.21-3.19 (m, 2H), 3.91 (s, 3H), 4.17-4.11 (m, 2H), 4.31 (br, 1H), 4.98 (s, 2H), 5.57 (br, 1H), 6.73 (s, 1H), 7.57-7.34 (m, 7H), 10.07 (s, 1H).
Reaction SMILES: [H][H].[C:3]1([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1.C1(=C2CCCCC2=O)CCCCC1.C1(C2C=CC=CC=2O)C=CC=CC=1>O>[CH:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: O=C1CCCCC1C1=CCCCC1
Agent: O=C1CCCCC1=C1CCCCC1
Agent: Oc1ccccc1-c1ccccc1
Solvent: O
Product: Oc1ccccc1C1CCCCC1
Reaction time: 68 h
Yield: 0.5 %

Procedure:
27 g of the catalyst prepared according to Example 1 were additionally impregnated with a solution of 0.81 g of K2SO4 in 10 ml of water and then dried at 120° C. for 20 hours. 30 ml (25.5 g) of the catalyst thus prepared were heated to 400° C. in a stream of hydrogen (10 l/hour), using the reaction tube described in Example 1, and were kept at this temperature for 68 hours. The oven temperature was then reduced to 350° C. and the dehydrogenation reaction was carried out without a carrier gas. 11.7 g/hour of the isomer mixture 2-cyclohexenylcyclohexanone and 2-cyclohexylidenecyclohexanone were thereby used. 3,972 g of reaction product containing 92.3% of o-phenylphenol and 0.5% of cyclohexylphenol were obtained in the course of 358 hours.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)=[O:7])C.[Li+].[OH-]>CO.O.C1COCC1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH:5]([O:18][CH2:19][CH3:20])[C:4]([OH:21])=[O:3])=[CH:15][CH:14]=1)#[N:17]
Reactant: CCOC(=O)C(OCC)C(=O)NCc1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(C(=O)O)C(=O)NCc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid ethyl ester (1.97 g) and LiOH (285 mg) in MeOH (14 ml), H2O (7 ml) and THF (14 ml) was stirred 3 h at 60° C. The solvents were evaporated, EtOAc was added and it was washed with HCl 0.1 N, water and brine. The aqueous phases were extracted again with more EtOAc. The combined organic phases were dried (MgSO4) and the solvent was removed to yield (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid, 1.53 g (86%); of white solid. MS 260.2 (100, [M+H]+), 277.2 (13, [M+NH4]+)
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH:12](O)[CH2:13][NH:14][C:15]([NH:21]C(OC)=O)=[N:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C.S(Cl)(C)(=O)=O>CO>[CH3:20][O:19][C:17]([NH:16][C:15]1[NH:21][CH:12]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:11])[CH2:13][N:14]=1)=[O:18]
Reactant: COC(=O)N=C(NCC(O)c1c(Cl)cccc1Cl)NC(=O)OC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)NC1=NCC(c2c(Cl)cccc2Cl)N1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To 5 l of a methylene chloride solution containing 550 g of 1-(2',6'-dichlorophenyl)-2-(2',3'-bis-methoxycarbonylguanidino) ethanol was added 530 ml of triethylamine. The mixture was stirred until a clear solution formed. Mesyl chloride, 160 ml was then added dropwise with stirring at such a rate that the solution temperature did not pass 35° C. The reaction was complete after 30 minutes. One liter of methanol was added to the reaction mass and the resulting mixture filtered. To the filtrate was added 4 l of methanol and a solution of 270 g of sodium hydroxide in 550 ml of deionized water. The mixture was vigorously agitated and heated to about 40° C. for one hour. The reaction solution was then vacuum distilled until approximately 5 l of distillate had been collected. After addition of 8 l of deionized water to the distillation flask, vacuum distillation was continued, collecting 3 l of distillate. The pot residue was cooled to about 20° C. and stirred for about 1 hour. The imidazole product precipitated from the residual reaction solution and was filtered, washed with 3 l of deionized water then 1 liter of methanol. Drying at 65° C. in a vacuum oven gave 403 g of 4,5-dihydro-2-methoxycarbonylamino-5-(2',6'-dichlorophenyl)imidazole, m.p. 231°-232° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:20])=[CH:17][CH:16]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1ccc(C(=O)O)cc1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(C(=O)NC2CCOCC2)cc1
Yield: 88 %

Procedure:
As described for example 7b, 4-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 281 mg, 88%) which was obtained as a white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([C:28]2[N:32]([CH3:33])[N:31]=[N:30][N:29]=2)[CH:10]=[CH:11][C:12](=[O:27])[CH2:13][CH:14]([OH:26])[CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:42]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[C:9]([C:28]2[N:32]([CH3:33])[N:31]=[N:30][N:29]=2)[CH:10]=[CH:11][C:12](=[O:27])[CH2:13][CH:14]([OH:26])[CH2:15][C:16]([O-:18])=[O:17])=[CH:6][CH:7]=1.[Na+:42]
Reactant: Cn1nnnc1C(C=CC(=O)CC(O)CC(=O)OCc1ccccc1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=CC(=O)CC(O)CC(=O)[O-])=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 24 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
Phenylmethyl 9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoate (0.34g, 0.62 mmole) was dissolved in tetrahydrofuran (4mL) and water (1mL). 1N Sodium hydroxide (0.62 mL, 0.62 mmole) was added, and the solution was stirred for 6 hours at 24° C. The mixture was diluted with water (10 mL) and washed with diethyl ether (3×50 mL). The aqueous portion was lyophilized to give 0.17 g (52%) of the title compound; m.p.=166°-180° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]#[N:24])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 46.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.033 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]=[C:6]1[C:15]2[CH:14]=[C:13]([Cl:16])[S:12][C:11]=2[C:10]([O:17][CH3:18])=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)C.[OH-].[Na+]>C(O)C>[Cl:16][C:13]1[S:12][C:11]2[C:10]([O:17][CH3:18])=[CH:9][C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[C:6](=[CH:5][C:4]([OH:23])=[O:3])[C:15]=2[CH:14]=1
Reactant: CCOC(=O)C=C1c2ccccc2C=C(OC)c2sc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC1=Cc2ccccc2C(=CC(=O)O)c2cc(Cl)sc21

Procedure:
14 g of the product of example 1 [(Z)/(E)isomer mixture] or of example 2 [(Z) or (E) isomer individually] are dissolved in 140 ml ethanol, combined with 70 ml 2N NaOH and heated for 3 hours under reflux. The obtained solution is evaporated down to 1/3 volume and poured onto 250 ml ice water. The aqueous phase is adjusted to pH 1 by addition of 4N HCl and the obtained precipitate filtered off, washed with H2O and dried to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1.[C:21]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C(#N)C>[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:21]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1)=[O:31])([OH:26])=[O:25]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COCCc1nc(Cl)c(CO)n1Cc1ccc(N)cc1
Solvent: CC#N
Product: COCCc1nc(Cl)c(CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an acetonitrile solution (12 mL) of 1-(4-aminobenzyl)-4-chloro-5-hydroxymethyl-2-(2-methoxyethyl)imidazole (150 mg, 0.51 mmol) was added an acetonitrile solution (2 mL) of phthalic anhydride (75 mg, 0.51 mmol). After stirring overnight at room temperature a light yellow precipitate was produced. The mixture was cooled to 0°, filtered with suction onto a fine fritted funnel and the solid was washed with cold acetonitrile, chloroform and finally ether (2 mL each) to afford 180 mg (80%) of light tan solid, m.p. 185°-186° (dec.). NMR (200 MHz, CDCl3 /CD3OD) δ 8.05-6.95 (m, 8H); 5.30 (s, 2H); 4.50 (s, 2H); 3.60 (t, 2H, 5Hz); 3.25 (s, 3H); 2.8 (t, 2H, 5Hz). Mass Spec. Calcd. for C22H18ClN3O3 (M-2H2O):4.07.1037. Found: 407.1031.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH3:5].[C:6]1([C:12]2[O:13][CH2:14][C@H:15]([CH2:17][OH:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N[C@H](C(O)=O)CO>C1COCC1.O>[CH2:4]([O:18][CH2:17][C@H:15]1[CH2:14][O:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:16]1)[CH3:5]
Reactant: CCI
Reactant: OC[C@H]1COC(c2ccccc2)=N1
Agent: N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@H]1COC(c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of sodium hydride (354 mg, 8.86 mmol) and iodoethane (0.90 ml, 11.2 mmol) in anhydrous THF (22 mL) was chilled to 0° C. A solution of (S)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (785 mg, 4.43 mmol) (Synthesis, 1993, 2, 250-262; using D-, instead of L-serine as a starting material) in 10 ml anhydrous THF was then added dropwise to the reaction mixture. The resulting mixture was allowed to warm to ambient temperature, and stirred overnight. After addition of water, the mixture was extracted with EtOAc. The combined organic extracts were dried and concentrated to afford (S)-4-(ethoxymethyl)-2-phenyl-4,5-dihydrooxazole as a clear, light-brown oil (0.981 g, 108%), which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:27]([O:29]C)=[O:28])[C:12]2[CH2:13][CH2:14][N:15]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:16](=[O:19])[C:17]=2[CH:18]=1)#[N:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:27]([OH:29])=[O:28])[C:12]2[CH2:13][CH2:14][N:15]([CH:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])[C:16](=[O:19])[C:17]=2[CH:18]=1)#[N:2]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3ccccc3C#N)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(-c3ccccc3C#N)cc2C1=O
Yield: 99.5 %

Procedure:
178 mg of methyl 7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are dissolved in 3.6 cm3 of dioxane at a temperature close to 20° C. 1.1 cm3 of a 1N aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 30 min. The mixture is then concentrated to dryness under reduced pressure (5 kPa), taken up by 20 cm3 of water and 20 cm3 of ethyl ether. The aqueous phase is washed with 5 cm3 of ethyl ether, acidified with 2 cm3 of a 2N aqueous solution of hydrochloric acid and taken up with 10 cm3 of dichloromethane. The organic phase is extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 171 mg of 7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a white foam.
Reaction SMILES: O[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(S(F)(F)[F:16])CC)C>C(Cl)Cl>[F:16][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)F
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Ethyl 2-hydroxyisobutyrate (12.43 g) was stirred in dry methylene chloride (65 ml) at -70° C. under nitrogen. Diethylaminosulphur trifluoride (30.32 g) in dry methylene chloride (5 ml) was added slowly, maintaining the temperature at -70° C. After completion of the addition, the mixture was stirred at -70° C. for 1 hour and was then allowed to warm to room temperature, stood for 3 hours and then overnight. The reaction was then carefully added to ice with vigorous stirring, and the resultant methylene chloride layer combined with a further methylene chloride extract of the aqueous layer. The total organic fraction was washed with brine, dried over magnesium sulphate and the solvent carefully distilled, to leave ethyl 2-fluoro-isobutyrate as a bronze liquid (12.8 g); 1H NMR analysis indicated that this material was >95% pure, and contained 2-3% of ethyl methacrylate. NMR (CDCl3, 270 MHz) δ 1.31(3H,t), 1.58(6H,d), 4.25(2H,q) ppm; 1H NMR (CDCl3, 254 MHz, 19F) δ -148.0 (1F, septet) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:9][C:4]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1NCCO
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(F)c1NCCO

Procedure:
To a solution of 2-[(2,3-difluoro-6-nitrophenyl)amino]ethanol (3.8 g, 17.4 mmol) in 70 ml of ethyl acetate and 30 ml of ethanol is added 10% Pd/C (380 mg). The reaction is shaken under 50 PSI of hydrogen for 3 hours. The pressure is periodically adjusted to 50 PSI. The reaction is filtered through celite, rinsed with ethanol and concentrated. The resulting material is used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 3.17-3.27 (m, 2H) 3.68-3.78 (m, 2H) 6.38 (ddd, J=8.89, 4.69, 2.05 Hz, 1H) 6.61-6.70 (m, 1H)
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CC(C)([O-])C.[K+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([CH3:40])[CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([O:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:24])=[CH:33][C:34]=1[CH3:40])#[N:37]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCO)ccc21
Reactant: Cc1cc(F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCOc3ccc(C#N)c(C)c3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-methylpentanamide (0.34 g, 1.05 mmol) in DMF (8.0 mL) was added potassium-t-butoxide (0.258 g, 2.31 mmol) under argon atmosphere. The mixture was stirred at room temperature for 15 min, and 4-fluoro-2-methylbenzonitrile (0.212 g, 1.57 mmol) was added thereto. The reaction solution was stirred at room temperature for 14 hr, and ethyl acetate (80 mL) was added thereto. The organic layer was washed with cold water (2×20 mL) and saturated brine (2×20 mL), and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 30% ethyl acetate/hexane) to give the title compound (0.16 g, 35%) as a white powder.