Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:73][O:74][C:75]1[CH:86]=[C:85]2[C:78]([NH:79][CH:80]=[C:81]2[CH2:82][CH2:83][NH2:84])=[CH:77][CH:76]=1>CN(C=O)C>[CH3:73][O:74][C:75]1[CH:86]=[C:85]2[C:78](=[CH:77][CH:76]=1)[NH:79][CH:80]=[C:81]2[CH2:82][CH2:83][NH:84][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:1]#[N:2])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCNC(=O)C(CC(C)C)Oc3ccc(C#N)c(C(F)(F)F)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound was prepared in the following manner. To 0.25 gm (0.83 mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid in dimethylformamdie “DMF” (15 mL) were added 0.14 gm (1.04 mmol) of 1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.04 mmol) of (3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.28 mmol) N-methyl morpholine, and approximately 234 mg of 5-methoxytryptamine hydrochloride (1.04 mmol). The resultant mixtures were stirred at room temperature for approximately 18 hours. The reactions were quenched with sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20 mL). The solvent was removed in vacuo to obtain oils that were then purified by HPLC.
Reaction SMILES: C([N:22]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][C:24]([OH:26])=[O:25])(=O)C=CC=CC=CC=CC=CCCCCCCCCC.C(N(C1C=CC(O)=CC=1)CC(O)=O)(=O)C=CC=CC=CC=CC=CC=CCCCCCCCCC>>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)N(CC(=O)O)c1ccc(O)cc1
Agent: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)N(CC(=O)O)c1ccc(O)cc1
Product: O=C(O)CNc1ccc(O)cc1

Procedure:
The same procedure as in Example 5 but EPA-Cl was replaced by 4.2 g (0.012 mole) of the mixture of polyunsaturated fatty acyl chlorides as prepared in Example 4. Yield of the mixed product was about 88 percent, containing N-eicosapentaenoyl (4-hydroxyphenyl)-glycine and N-docosahexaenoyl (4-hydroxyphenyl)-glycine as the main components.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[O:14][C:13]([CH:16]3[CH2:18][CH2:17]3)=[N:12][C:11]=2[C:10]([C:19]#[N:20])=[C:9]([CH3:21])[C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.C(N(CC)CC)C.[CH2:37]([OH:40])[CH:38]=[CH2:39]>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]1([C:13]2[O:14][C:15]3[C:11](=[C:10]([C:19]#[N:20])[C:9]([CH3:21])=[C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:7]=3[C:38]([CH2:37][OH:40])=[CH2:39])[N:12]=2)[CH2:17][CH2:18]1
Reactant: C=CCO
Reactant: Cc1c(-c2ccccc2)c(OS(=O)(=O)C(F)(F)F)c2oc(C3CC3)nc2c1C#N
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(CO)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
4-Cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl trifluoromethanesulfonate (I-323) (760 mg, 1.80 mmol) was dissolved in dimethylformamide (10 ml), then triethylamine (276 μl, 1.98 mmol), allyl alcohol (209 mg, 3.60 mmol), 1,1′-bis(diphenylphosphino)ferrocene (79.8 mg, 0.144 mmol) and palladium(II) acetate (24.2 mg, 0.108 mmol) were added, followed by stirring in an oil bath at 100° C. under argon atmosphere for 16 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1, v/v) to obtain the entitled compound (193 mg, 32%) as a colorless oily substance.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([O:16][CH2:17][C:18]#[CH:19])(=[O:15])[CH3:14]>CCOCC>[C:13]([O:16][CH2:17][C:18]1[CH:19]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1)(=[O:15])[CH3:14]
Reactant: C#CCOC(C)=O
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: CCOCC
Product: CC(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Reaction time: 0.5 h

Procedure:
2.0 g of diazooxindole (0.013 mole) and 12.8 g (0.13 mole or 10 equivalents) of propargyl acetate are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with 200 ml of ether, stirred for 30 minutes and filtered. The light tan product is washed with ether, dried in vacuo for 1 hour at room temperature and treated with activated charcoal in a mixture of ethanol (200 ml) and ethyl acetate (100 ml). The reaction mixture is filtered through a Celite pad, concentrated to a volume ~100 ml, diluted with 100 ml ethyl acetate and concentrated to a volume of 50 ml. Another 100 ml of ethyl acetate is added, the resulting solution is concentrated to a volume of 50 ml and cooled to 0°-5°. The title compound is filtered off and dried.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH:17]([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:20]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=[C:7]([I:20])[C:6]=1[O:15][CH2:16][CH:17]([F:18])[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(F)F)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(I)c(OCC(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 100.1 %

Procedure:
2,4-Di-tert-butyl-1-(2,2-difluoro-ethoxy)-benzene (6.75 g, 25 mmol), N-iodosuccinimide (6.74 g, 30 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) were combined in dichloromethane (75 mL) and heated at 38° C. for 7 h. TLC (hexanes) indicated a small amount of starting material still present and the reaction was treated with additional N-iodosuccinimde (0.33 g). After 4 h the reaction was washed with 10% Na2SO2O3 solution (50 mL). The aqueous was backwashed with dichloromethane (100 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide an orange oil (9.92 g). The material was purified by flash chromatography using hexane to give 8.88 g (90%) of a light pink oil which solidified over time. 1H NMR (250 MHz, CDCl3): δ 7.66 (d, 1H, J=2.4), 7.36 (d, 1H, =2.4), 6.29 (tt, 1H, J=55.3, J=4.3), 4.24 (td, 2H, J=13.2, J=4.3), 1.40 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][Zn]C>O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Reactant: C[Zn]C
Solvent: C1CCOC1
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(C)cccc23)n1
Temperature: 60 °C
Yield: 32 %

Procedure:
To a solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (80 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (304 μL, 2.0 M in toluene, 0.60 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.02 mmol). The reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled, then quenched with ice water. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:1 hexanes:ethyl acetate) provided N-butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (24 mg, 32%) as a yellow solid. Rf 0.33 (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 8.04 (d, 1H), 7.64 (m, 2H), 7.27 (m, 1H), 7.13 (t, 2H), 6.77 (d, 1H), 6.31 (d, 1H), 5.17 (br, 1H), 3.48 (m, 2H), 2.80 (s, 3H), 1.65 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H); MS m/z 376 (M+1).
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[NH:25]([CH2:27][CH2:28][OH:29])[NH2:26]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[N:25]([CH2:27][CH2:28][OH:29])[N:26]=2)[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reactant: NNCCO
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A solution of 45.2 g of 4-(2-chloronicotinoyl)2,6-di-tertiary butylphenol and 21 g of 2-hydrazinoethanol in 230 ml of pyridine is refluxed under stirring for 18 hours. After completion of the reaction, the pyridine is concentrated and 140 ml of ethanol and 70 ml of water are added to the residue. The mixture is warmed to dissolve and then cooled to 0° C. The precipitated crystals are collected by filtration, recrystallized from 70% dioxane and then dried to give 40 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridine, melting at 135°-137° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:5]=[CH:4][C:3]1=2.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[N:7]=[C:8]3[C:3]([CH:2]([CH3:1])[CH2:11][C:10](=[O:12])[NH:9]3)=[CH:4][CH:5]=2)[CH2:30][CH2:29]1
Reactant: CC1CC(=O)Nc2nc(OCCCC=O)ccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1CC(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
The crude 4-(5-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde in 1,2-dichloroethane (50 mL) is treated with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.104 g, 4.13 mmol), followed by triethylamine (0.80 mL, 5.69 mmol) and sodium triacetoxyborohydride (0.911 g, 4.30 mmol). The cloudy yellow solution is stirred at room temperature for 1 hour. The mixture is quenched with water and saturated NaHCO3 solution and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to a yellow oil. The oil is purified by column chromatography (5:95 methanol/ethyl acetate) to afford the title compound (1.08 g, 79% over 2 steps) as a white solid. Mp 53–54° C. 1H NMR (CDCl3, 400 MHz): δ 8.94 (br s, 1H), 7.83 (d, 1H), 7.18–7.13 (m, 2H), 6.98–6.94 (m, 1H), 6.62 (d, 1H), 6.38 (d, 1H), 4.38 (t, 2H), 3.16–3.02 (m, 4H), 2.76–2.60 (m, 4H), 2.55–2.46 (m, 2H), 1.90–1.82 (m, 2H), 1.77–1.64 (m, 2H). MS ES: m/z=462.72, 464.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[BH3-]C#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2ncccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCCN2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Based on G. W. Gribble, et al., Synthesis, 1975, 650-652, 6-methoxyquinoline (1.26 g, 7.9 mmol) was dissolved in glacial acetic acid (20 mL) under N2 at RT. Solid NaCNBH3 (2 g, 32 mmol) was added in small portions over a 45 min period. The reaction was heated to 50° C. for 8 h, then cooled to RT and stirred overnight. The reaction was quenched by cooling it to 0° C., and the pH of the solution was adjusted to 14 with 2 N NaOH. The solution was extracted 3 times with EtOAc. The EtOAc extracts were washed brine, combined, dried over Na2SO4, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (5% and 10% EtOAc/Hexane step gradient) giving 6-methoxy-1,2,3,4-tetrahydroquinoline as a red oil. This material was used without further purification.
Reaction SMILES: [CH2:1]([N:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]2([CH2:20]C[C:18](=[O:21])[C:17]3[C:9]2=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=3)[C:7]1=[O:28])[CH2:2][CH2:3][CH2:4][CH3:5].[BH4-].[Na+].O>CO>[OH:21][CH:18]1[C:17]2[C:9](=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)[C:8]2([C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[O:28])[CH2:20]1
Reactant: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCN1C(=O)C2(CC(O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione (0.20 g, 0.55 mmol) in methanol (10.0 mL) was added sodium borohydride (0.03 g, 0.83 mmol). The reaction mixture was stirred at ambient temperature for 2 h and poured into of water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.18 g, 90%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.36-7.29 (m, 1H), 7.11-6.99 (m, 3H), 6.93 (d, 1H), 5.98 (s, 1H), 5.94-5.87 (m, 2H), 5.16 (d, 1H), 3.80-3.61 (m, 2H), 2.69 (br, 1H), 2.39 (d, 1H), 1.75-1.62 (m, 2H), 1.38-1.22 (m, 4H), 0.87 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.5, 148.9, 148.5, 143.7, 140.5, 136.9, 132.1, 128.7, 123.7, 123.3, 108.8, 105.7, 103.2, 101.5, 74.8, 59.6, 40.4, 28.9, 27.0, 22.3, 14.0; MS (ES+) m/z 388.4 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([Mg]Br)[CH:7]=[CH:6]2.[Cl-].[Zn+2:16].[Cl-]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([Zn:16][C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([Mg]Br)ccc2c1
Reactant: [Zn+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2cc([Zn]c3ccc4cc(OC)ccc4c3)ccc2c1

Procedure:
The resulting solution of 6-methoxy-2-naphthylmagnesium bromide in 50 ml. of benzene under nitrogen is added 3.14 g. of anhydrous zinc chloride. The temperature of the mixture is maintained at a temperature of from 25°-30°C for 1 hour, yielding a solution of di-(6-methoxy-2-naphthyl)zinc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]CC)=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 5 °C
Yield: 66 %

Procedure:
Crude ethyl 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxylat (30 g) is dissolved in EtOH (96%, 150 ml) and aqueous 2N NaOH (150 ml). The solution is refluxed for 1 hour. ½ of the volume is removed in vacuo. The aqueous phase is extracted with EtOAc (2×100 ml). The aqueous phase is made acidic (pH=1, conc. HCl) and after cooling to 5° C. the white crystals are filtered off. Yield 16 g. Overall yield is 66% starting from 5-ethoxycarbonylphthalide. Mp 187-190° C.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].[CH3:16][C:17](=O)[CH2:18][CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C>[CH3:21][C:20]1[N:2]([NH:1][C:3]2[N:4]=[N:5][C:6]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:7][CH:8]=2)[C:17]([CH3:16])=[CH:18][CH:19]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CN1CCN(c2ccc(NN)nn2)CC1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CCN(C)CC2)nn1
Temperature: 70 °C

Procedure:
A mixture of 7 g (35 m moles) of 3-hydrazino-6-(4-methyl-1-piperazinyl)-pyridazine and 4.1 g (36 m moles) of 2,5-hexanedione in 100 ml of acetic acid is heated for 3 hours at 70° C. The solvent is evaporated off under vacuum and the oily residue is dissolved in water and made alkaline with 10% sodium hydroxyde. The mixture is extracted with ethyl acetate and the organic layer is evaporated to dryness in vacuo. The solid residue is crystallized first from ethyl ether and then from ethyl acetate yielding 2.6 g (26%) of the product of the title which melts at 181°-182° C.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]([N:41]1[CH2:46][CH:45]=[C:44]([C:47]([CH3:51])([CH3:50])[CH:48]=O)[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>O1CCCC1.O>[CH2:34]([N:41]1[CH2:46][CH:45]=[C:44]([C:47]([CH3:51])([CH3:50])[CH2:48][CH:2]=[O:3])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)C1=CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CC=O)C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.9 %

Procedure:
Step E To a mixture of methoxymethyl triphenylphosphonium chloride (12.6 g, 37 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (46 mL, 46 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0° C. for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionaldehyde (5.6 g, 23 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HCl solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-butyraldehyde as a yellow oil (1.65 g, 28%).
Reaction SMILES: C([O:3][C:4](=[O:46])[C@@H:5]([CH3:45])[CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[C:9]2[CH:36]=[C:37]([CH3:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:8]1=2)C.[OH-].[Na+]>CO.O>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)[CH2:21][N:14]([C:15]1[N:16]=[N:17][N:18]([CH3:20])[N:19]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][C@H:5]([CH3:45])[C:4]([OH:46])=[O:3])[C:8]2[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[C:37]([CH3:44])=[CH:36][C:9]1=2
Reactant: CCOC(=O)[C@@H](C)CN1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(C[C@H](C)C(=O)O)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2-methyl-propionic acid ethyl ester (Example 112) (0.04 mmol) in methanol (5 mL), add 5.0 N sodium hydroxide (2 mL). After heating at 60° C. for 6 h cool to room temperature and dilute with water (20 mL). Extract the organics with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum, to afford the title compound as a mixture of diastereomers. MS (ES+): 639 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:6][C:5]=1[Br:20].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:15])[CH3:16])=[CH:6][C:5]=1[Br:20]
Reactant: CCC(C)(C)NCC(=O)c1cc(F)c(N)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)NCC(O)c1cc(F)c(N)c(Br)c1

Procedure:
m.p. of the hydrochloride: 185°-187° C. (decomp.), was prepared from 4'-amino-3'-bromo-5'-fluoro-2-tert.pentylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([C:4]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:3].C1CCCCC=1>C1COCC1.[Pd]>[CH3:8][C:6]([CH3:9])([C:5]([C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[C:4]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[C:2]([CH3:1])([CH3:3])[CH3:28])[CH3:7]
Reactant: CC(C)(C)C(=C(c1ccc([N+](=O)[O-])cc1)C(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)C(=C(c1ccc([N+](=O)[O-])cc1)C(C)(C)C)c1ccc(N)cc1
Yield: 49.9 %

Procedure:
A solution of 0.62 g 2,2,5,5-tetramethyl-3,4-di(4-nitrophenyl)hex-3-ene,2.6 g cyclohexene and 1.4 g 10% Pd/C in THF was refluxed for 2 hrs. The Pd/C was removed by filtration and the residue after evaporation of the solvent was purified by chromatography on silica gel (25% CH2Cl2 -hexane) to give 0.285 g (50%) 2,2,5,5-tetramethyl-3-(4-nitrophenyl)-4-(4-aminophenyl)hex-3-ene: 1H NMR (CDCl3): δ0.66 (s, 8H), 0.70 (s, 8H), 3.61 (s, 2H), 6.61-6.63 (d, 2H), 7.30-7.34 (d, 2H), 8.12-8.14 (d, 2H): 13C NMR (CDCl3): δ32.81, 32.84, 37.59, 38.16, 113.58, 121.93, 131.34, 131.48, 133.12, 143.78, 144.58, 146.22, 146.88, 152.11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[NH2:17][CH2:18][C:19](OCC)=[O:20]>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2=[C:2]([CH:7]=1)[NH:1][C:19](=[O:20])[CH2:18][N:17]=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CN
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Solvent: c1ccncc1
Product: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Yield: 50.8 %

Procedure:
(2-Amino-4-bromophenyl)(phenyl)methanone (1.75 g, 10 mmol), ethyl 2-aminoacetate (2.23 g, 16 mmol) and pyridine (40 mL) were stirred together at 80° C. for about 3 days. The pyridine was evaporated and the residue was triturated in 5% methanol in ethyl acetate to afford title compound 354 (1.6 g, 51%) as a yellow solid.