Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH:18]([CH3:20])[CH3:19])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH:18]([CH3:20])[CH3:19])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@]1(C(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of methyl (1S,4S)-4-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopent-2-ene-1-carboxylate (18.42 g, 65 mmol) in THF (500 mL), methanol (500 mL) and water (100 mL) was added lithium hydroxide monohydrate (5.00 g, 119 mmol). The mixture was heated to reflux overnight. After 18 hours, TLC indicated a very trace amount of starting material. The organic solvents were removed in vacuo and the aqueous layer was extracted with ether (200 mL) to remove the unreacted starting material. The aqueous layer was acidified with concentrated HCl to pH=4 while being cooled in an ice bath. The resulting solution was extracted with methylene chloride three times. The extracts were dried over MgSO4 and concentrated to give a solid (17 g). The solid was dissolved in hot ethyl acetate (22 mL) and hexanes (550 mL) were added to the solution. The solution was slowly cooled down to room temperature before putting into a freezer reading at −22 to −24° C. After two days, the crystals were removed off and the liquid was evaporated in vacuo to give the desired product as a white foamy solid (9.78 g, 56%). MS calculated for C14H23NO4: (M+H)+ 270; found 170.1 (M-Boc+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[O:12][C:13]1[CH:14]=[C:15]([CH3:27])[C:16]2[CH:20]([CH2:21][C:22]([OH:24])=[O:23])[O:19][B:18]([OH:25])[C:17]=2[CH:26]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:25][B:18]1[C:17]2[CH:26]=[C:13]([O:12][C:11]3[CH:28]=[CH:29][CH:30]=[C:9]([OH:8])[CH:10]=3)[CH:14]=[C:15]([CH3:27])[C:16]=2[CH:20]([CH2:21][C:22]([OH:24])=[O:23])[O:19]1
Reactant: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc2c1C(CC(=O)O)OB2O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(Oc2cccc(O)c2)cc2c1C(CC(=O)O)OB2O
Yield: 58.5 %

Procedure:
A solution of [6-(3-benzyloxy-phenoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.55 g, 1.36 mmol) and 10% Pd/C (0.4 g) in EtOH (100 mL) was hydrogenated at 40 psi for 30 minutes. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (MeOH:DCM 10:90) to give [1-hydroxy-6-(3-hydroxy-phenoxy)-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.25 g, 58%). mp 138.2-140.1° C. 1H NMR (400 MHz, DMSO): δ 12.34 (s, 1H), 9.59 (s, 1H), 9.19 (s, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.53 (dd, J=8.4, 2.0 Hz, 1H), 6.42 (dd, J=8.0, 2.0 Hz, 1H), 6.35 (t, J=2.4 Hz, 1H), 5.48 (dd, J=9.2, 2.4 Hz, 1H), 3.09 (dd, J=15.2, 2.4 Hz, 1H), 2.28 (s, 3H), 2.14-2.07 (m, 1H). MS (ESI) m/z: 315 (M+1)+. HPLC purity: 98.56% (Maxplot), 98.87% (220 nm).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][NH:17][C:16](=[O:19])[C:15]=2[CH2:20][CH3:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].[PH2](O)=O.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.[Cu-]=O>[CH2:20]([C:15]1[C:16](=[O:19])[NH:17][CH2:18][C:14]=1[C:4]1[CH:3]=[CH:2][C:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:6][CH:5]=1)[CH3:21]
Reactant: CCC1=C(c2ccc(-n3ccnc3C)c(N)c2)CNC1=O
Agent: O=[Cu-]
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCC1=C(c2ccc(-n3ccnc3C)cc2)CNC1=O
Reaction time: 0.08 h

Procedure:
4-[3-Amino-4-(2-methyl-1H-imidazol-1-yl)phenyl]-3-ethyl-1,5-dihydro-2H-pyrrol-2-one (2.0 g, 7.1 mmol) is dissolved in concentrated HCl (40 mL) at 5° C, and hypophosphorous acid (50% aqueous solution, 14.6 mL, 0.14 mol) is added dropwise. Aqueous sodium nitrite (2 N, 4.4 mL, 8.8 mmol) is added, and the mixture is stirred for 5 minutes. A trace amount of copper (I) oxide is added, and the mixture is stirred an additional 1 hr at 5° C. The mixture is neutralized with sodium carbonate, extracted with n-butanol, and the extracts are evaporated. The residue is triturated with methanol, filtered, and the filtrates are evaporated. Chromatography of the residue on silica gel followed by recrystallization from ethanol and drying under vacuum at 70° C. for 18 hr provides the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:35])([F:34])[CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][C:28]([F:35])([F:34])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CCC(F)(F)F
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (79 mg, 70%), MS (ISP) m/z=453.3 [(M+H)+], mp 200° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4,4,4-trifluoro-butyric acid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.B(O)(O)O.O>C1(C)C(C)=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(-c2noc3ccccc23)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccc(N=Cc2ccc(-c3noc4ccccc34)cc2)cc1
Temperature: 60 °C

Procedure:
22.32 g of 3-(p-formylphenyl)-1,2-benzisoxazole, 14.03 g of p-chloroaniline and 0.5 g of boric acid in 160 ml of xylene are refluxed for 2 hours, the water formed being distilled off. The mixture is cooled to 60° C., 500 ml of methanol are added and the resulting mixture is further cooled to -10° C. The product which has precipitated is filtered off with suction, washed with 100 ml of cold methanol and dried. This gives 32 g (96.2% of theory) of compound (102) in the form of pale yellow crystals which melt at 164° to 165° C. After recrystallising twice from toluene, pale yellow crystals with a melting point of 164.5° to 165° C. are obtained.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:19][CH:18]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccccc2Cl)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1ccccc1C1=CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(2-chlorophenyl)-1 ,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]([Mg]Br)=[CH2:18].[Cl-].[NH4+].C(OCC)C>C1COCC1.O>[CH:17]([C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[CH2:18]
Reactant: C=C[Mg]Br
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=CC1(O)c2ccccc2CCc2ccccc21

Procedure:
A solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (9.4 g, 0.045 mol) in dry THF (100 ml) was placed under an atmosphere of nitrogen. A solution of vinylmagnesium bromide in THF (100 ml, 0.5 M) was added in such a rate to keep the reaction temperature at 30°-35° C. When addition was complete the mixture was heated at 50°-60° C. for 1.5 h. The reaction mixture was cooled on an ice-bath and a solution of ammonium chloride (10 g) in water (50 ml) was carefully added. Diethyl ether (100 ml) was added and the phases were separated. The aqueous phase was extracted with diethyl ether (100 ml) and the combined organic phases were dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue which was re-evaporated twice with dichloromethane to give 11.8 g of crude 5-ethenyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][C:20]=2[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>O1CCCC1.CO>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][C:20]=2[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCCC)c1
Yield: 74 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[3′-(1-methyl-3-pentylureido)-2-pentyloxybiphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 312 mg of 3-[3′-(1-methyl-3-pentylureido)-2-pentyloxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=83° C.). Yield=74% over the two steps.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(C)C=CC=CC=1.[CH2:20]1[O:23][C@H:21]1[CH3:22].C1CCCCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCN(C(C)C)C(C)C>[OH:23][C@@H:21]([CH3:22])[CH2:20][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: C[C@H]1CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a suspension of N-hydroxyphthalimide (250 g, 1.53 mol), toluene (450 mL), tetrabutylammonium bromide (24.7 g, 76.6 mmol) and (S)-(−)-propylene oxide (214.7 mL, 3.07 mol) was added DIPEA (13.3 mL, 76.6 mmol). The reaction mixture was heated under nitrogen at reflux for 3 hours. The reaction mixture was concentrated in vacuo to obtain a yellow solid. The solid was dissolved in hot ethyl acetate and loaded onto a plug of flash silica (600 g) and the product eluted with diethyl ether (4 L). The ether solution was concentrated in vacuo to yield a pale yellow solid. The solid was dissolved in ethyl acetate (150 mL) at 75° C. and cyclohexane (300 mL) added. The solution was allowed to cool down to room temperature with stirring, causing a white solid to crystallise from the solution. The crystals were collected by filtration, washing with ethyl acetate/hexane (1:2). The solid was recrystallised using the conditions described previously to yield the product as a white crystalline solid (233 g, 69%). 1H NMR (CDCl3, 400 MHz) 7.89-7.83 (2H, m), 7.81-7.75 (2H, m), 4.22 (1H, dd, J=11.5, 2.3 Hz), 4.11-4.02 (1H, m), 3.93 (1H, dd, J=11.3, 9.2 Hz), 3.79 (1H, d, J=3.2 Hz), 1.18 (3H, d, J=6.4 Hz).
Reaction SMILES: [F:1][C:2]([F:15])([CH2:12][CH:13]=[CH2:14])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].[OH-:18].[Na+].OO>O1CCCC1.CCOCC.[Cl-].[Na+].O.O>[F:1][C:2]([F:15])([CH2:12][CH2:13][CH2:14][OH:18])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: C=CCC(F)(F)COCc1ccccc1
Agent: OO
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCCCC(F)(F)COCc1ccccc1
Yield: 54 %

Procedure:
To a mixture of (29) (16.8 g, 79 mmoles) and sodium borohydride (901 mg, 23.7 mmoles, 20% excess) in dry tetrahydrofuran (75 ml), kept under nitrogen at room temperature, borontrifluoride-ether complex (4.07 ml, 31.6 mmoles, 20% excess) is added over a period of 25 min. After standing for 13/4 hours at room temperature, the reaction mixture is slowly hydrolyzed with water (6 ml). Addition of 3N NaOH (10 ml) is followed by careful introduction of hydrogen peroxide (10 ml, 30%) at such a rate that the internal temperature does not exceed 40° C. The temperature is then allowed to return to room temperature, and the reaction mixture is diluted with ether and brine. Usual work-up affords a mixture of isomeric alcohols (17.2 g) which is separated by chromatography on silica (ethyl acetate/petroleum ether: 15/85, RF: 0.1) to give 9.8 g (54%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C[O:42][C:43]([C@@H:45]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[NH:52][CH2:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])=O.[O-]CC.[Na+].C(O)C.Cl>CN(C)C=O>[CH3:56][C:55]([CH3:58])([CH3:57])[CH2:54][CH2:53][N:52]1[C:17](=[O:18])[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:15])(=[O:14])[N:12]=2)=[C:43]([OH:42])[CH:45]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]12
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.315 mmol) and N-methylmorpholine (0.070 mL, 0.630 mmol) were added sequentially to a solution of cis-2-(3,3-dimethyl-butylamino)-cycloheptanecarboxylic acid methyl ester (0.076 g, 0.300 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.244 mL, 0.600 mmol) was added and the reaction mixture was heated to 60° C. for 2 h. After cooling to 25° C. and stirring for 16 h, the reaction mixture was slowly added to 1.0 M aqueous hydrochloric acid solution (50 mL) at 0° C. The resulting precipitate was collected by filtration and dried in vacuo, then was triturated with a small amount of methanol (ca. 0.5 mL) to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.096 g, 0.178 mmol, 59%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.01 (s, 9H), 1.41-2.25 (m, 12H), 2.72-3.00 (m, 1H), 3.06 (d, 3H, J=3.6 Hz), 3.06-3.33 (m, 1H), 3.40-3.50 (m, 1H), 3.94-4.10 (m, 1H), 7.02 (d, 1H, J=18.0 Hz), 7.20 (dd, 1H, J1=22.7 Hz, J2=13.4 Hz), 7.64 (t, 1H, J=7.5 Hz), 7.69 (d, 1H, J=7.7 Hz). LC-MS (ESI) calcd for C24H34N4O6S2 538.19, found 539.4 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26](O)=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23](/[CH:24]=[CH:25]/[C:26]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:29][CH:30]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: CCCCOc1ccc(C=CC(=O)O)cc1
Product: CCCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.67 g (16.7 mmol) of 4-butoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.04 g (yield of Compound 147 as pale yellow needles.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([O:24]CC)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:27])[N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:7]=1[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:27])[N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:7]=1[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)OCC)s3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate (0.91 g, 1.6 mmol) in tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1N sodium hydroxide solution (3 ml). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.78 g, 89.7%) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20].O>C1COCC1>[CH2:20]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)c1ccc(C#N)nc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4 mmol of 6-Cyanonicotinic acid were dissolved in THF. 1.5 eq. of Cs2CO3 were added he reaction stirred for 10 min. 1.5 eq allylbromide and a catalytic amount of KI were added he reaction heated to 100° C. for 4 h. The product was isolated via extraction from cetate/water.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[CH:10]([NH:12][O:13][CH3:14])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][CH:23]([F:33])[C:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]([CH3:32])[N:25]=1>ClCCl.O>[Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[CH:10]([N:12]([O:13][CH3:14])[C:29]([C:28]2[C:24]([CH:23]([F:33])[F:22])=[N:25][N:26]([CH3:32])[CH:27]=2)=[O:30])[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a stirred solution of trans N-{1-[2-(5-Chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.19 g; 0.83 mmol) prepared as described in example P18 and triethylamine (0.16 ml; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.16 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.31 g (97% of theory) of trans 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-methoxy-amide as a resin.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH3:15])[C:6]([CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:7][N:8]=1)[CH3:2].[BH4-].[Na+].Cl>O1CCCC1>[CH2:1]([S:3][C:4]1[N:5]([CH3:15])[C:6]([CH2:9][CH:10]([C:11]#[N:12])[C:13]#[N:14])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(C=C(C#N)C#N)n1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ncc(CC(C#N)C#N)n1C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
0.44 g of [(2-ethylthio-1-methylimidazol-5-yl)methylidene]malononitrile was dissolved in 10 ml of tetrahydrofuran, and 0.10 g of sodium borohydride was then added under ice-cooling. The mixture was stirred for 4 hours under ice-cooling. The reaction mixture was added to 0.5 N hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.32 g of [(2-ethylthio-1-methylimidazol-5-yl)methyl]malononitrile.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:3]=1.[NH4+].[Cl-]>CO.O1CCOCC1.O.[Fe]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[C:6]([C:8]#[N:9])[CH:5]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc(Br)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Yield: 76.9 %

Procedure:
0.184 g (0.0005 mol) of 6-bromo-4-(4-nitrobenzenesulphonyl)-pyridine-2-carbonitrile was dissolved in 10 ml of methanol/dioxane, treated with 0.37 g of iron powder and a solution of 0.37 g of NH4Cl in 10 ml of water and boiled at reflux for 2 hrs. Then, the reaction mixture was filtered and the filter cake was rinsed with methanol and ethyl acetate. The filtrate was concentrated and the residue was dissolved in ethyl acetate, washed with sat. NaHCO3 solution, water and sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.13 g (75%) of 4-(4-aminobenzenesulphonyl)-6-bromopyridine-2-carbonitrile as yellow crystals; m.p.: 186-188° C.