Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[CH3:19][C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23].BrN1C(=O)CCC1=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH2:40]>C(Cl)(Cl)Cl.CCOC(C)=O.CO>[CH3:23][C:22]1[N:40]=[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]2[C:21]=1[C:20](=[O:25])[CH3:19]
Reactant: Nc1ccccn1
Reactant: CC(=O)CC(C)=O
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)nc2ccccn12
Reaction time: 1 h
Yield: 35.5 %

Procedure:
1,1′-Azobis(cyclohexanecarbonitrile) (catalytic amount) was added to a solution of pentane-2,4-dione (1.00 g, 9.99 mmol) and N-bromosuccinimide (1.96 g, 10.99 mmol) in CHCl3 (20 mL). The reaction mixture was stirred for 1 hour, filtered and the filtrate was concentrated under reduced pressure. The residue was re-dissolved in a 1:1 mixture of THF/Et2O (20 mL), then pyridin-2-amine (723 mg, 7.68 mmol) was added and the reaction mixture was refluxed overnight. After cooling the solvent was removed under reduced pressure and the residue was purified by column chromatography, eluents EtOAc, then EtOAc-MeOH (96:4), to afford the title compound (475 mg 35% yield). 1H NMR (DMSO-d6) δ (ppm): 9.59 (dt, J=6.8, 1.4 Hz, 1H), 7.68 (dt, J=8.8, 1.2 Hz, 1H), 7.56 (ddd, J=8.8, 6.8, 1.4 Hz, 1H), 7.17 (td, J=6.8, 1.4 Hz, 1H), 2.72 (s, 3H), 2.58 (s, 3H). MS (m/z): 174.20 (calc) 175.1 (MH+) (found).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:15]([OH:17])=O)[CH2:13][CH3:14])=[O:10])[CH3:8])=[O:5])[CH3:3].[CH2:28]([O:35][CH2:36]C1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na].C(Cl)(Cl)Cl.C[OH:49]>C(O)C1C=CC=CC=1.O>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][CH:12]([C:15]([C:36]([O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:49])=[O:17])[CH2:13][CH3:14])=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: CO
Reactant: CC[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na]
Solvent: O
Solvent: OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)C(=O)OCc1ccccc1
Yield: 31 %

Procedure:
This compound was prepared from Z-Ala-Ala-Abu-OH in 31% yield by the procedure described in Example PKC1, except that benzyl oxalyl chloride was used in the Dakin-West reaction and sodium benzyloxide in benzyl alcohol was used for enol ester hydrolysis; single spot on tlc, Rf2 =0.40 (CHCl3 :MeOH=9:1); mp 124°-125° C.; MS, m/e=498 (M+ +1). Anal. Calcd. for C26H31O7N3.2/3 H2O: C, 61.28; H, 6.39; N, 8.24. Found: C, 61.14; H, 6.65; N, 7.94.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Cl

Procedure:
A mixture of 2-chloronicotinic acid (2-chloro-3-pyridylcarboxylic acid, 4.0 g, 25.4 mmol), oxalyl chloride (2.28 ml, 26.65 mmol) and two drops of DMF are stirred in chloroform (60 ml) for 30 minutes and subsequently refluxed for 45 minutes. The volatiles are distilled under reduced pressure to give crude 2-chloronicotinoyl chloride. This crude product is added to a mixture of diethyl malonate (3.85 ml, 25.38 mmol), magnesium chloride (2.4 g, 25.38 mmol) and triethylamine (7 ml, 50.77 mmol) in acetonitrile (25 ml) with cooling, such that the temperature does not rise above 15° C. After stirring for 24 hours the reaction mixture is diluted with ether and washed repeatedly with 1 M hydrochloric acid and brine. Drying of the organic phase over magnesium sulfate, filtering and evaporation of the solvents gives crude diethyl 2-(2-chloronicotinoyl)-malonate. This crude product is dissolved in DMSO (40 ml) and water (3 ml), and is heated at 140-150° C. for four hours. The mixture is poured onto crushed ice and the product is extracted using ether. Filtering of the ether phase over a pad of silicagel gives 3-acetyl-2-chloropyridine as a yellow oil; 1H-NMR (CDCl3, 300 MHz): 8.50 (dd, 1H); 7.91 (dd, 1H); 7.34 (ddd, 1H); 2.71 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30]>>[CH3:35][O:34][C:32]1[CH:31]=[C:29]([NH:30][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH:28]=[C:27]([O:26][CH3:25])[CH:33]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: COc1cc(NC(=O)c2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)c2)cc(OC)c1

Procedure:
The product from Example 33B and 3,5-dimethoxyaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 469 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:15][N:8]1[C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[S:11][CH2:10][C:9]1=[O:12]
Reactant: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Yield: 90 %

Procedure:
To a stirred suspension of 3,4-dihydro-7-nitro-2H-1,4-benzothiazin-3-one (Step 2, 4.7 g, 22.3 mmol) and potassium carbonate (3.70 g, 26.8 mmol) in dry DMF (40 mL) in an ice bath is added iodomethane (4.16 mL, 66.8 mmol). The reaction mixture is taken out of the ice bath and heated at 50° C. for 1-2h. The resulting mixture is allowed to cool down. Water (35 mL) and ice are added and the precipitate is filtered off and washed with water (10 mL). The resulting solid is dried under high vacuum to give the title compound as a yellow solid (4.5 g, 90%), MS m/z 225.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]=[C:4]([CH:7]([O:10][CH3:11])[O:8][CH3:9])[C:5]#[N:6].[CH3:12][O-:13].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:11][O:10][CH:7]([O:8][CH3:9])[CH:4]([CH:3]([O:13][CH3:12])[O:2][CH3:1])[C:5]#[N:6]
Reactant: COC=C(C#N)C(OC)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(OC)C(C#N)C(OC)OC
Temperature: 25 °C

Procedure:
In a mixed solvent of 100 ml of toluene and 50 ml of methanol was dissolved 7.85 g (50 mmoles) of 2-methoxymethylene-3,3-dimethoxypropanenitrile. To the resulting solution was added 9.65 g (50 mmoles) of a 28 wt. % solution of sodium methylate in methanol and the mixture was stirred at room temperature for one and a half hours. Subsequently, the reaction mixture was concentrated under reduced pressure to remove the methanol by distillation. To the resulting residue was added 25 ml of water and the toluene layer was separated followed by drying over anhydrous sodium sulfate. The thus dried toluene solution was distilled to obtain 8.50 g (45 mmoles) of 2-dimethoxymethyl-3,3-dimethoxypropanenitrile as a colorless transparent oil boiling at 90°-93° C./2 mmHg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.C[N:24]1CCOCC1.[NH2:30][CH:31]([CH2:35][C:36]1[N:37]=[N:38][NH:39][N:40]=1)[C:32]([OH:34])=[O:33]>CN(C)C=O>[NH4+:1].[NH4+:24].[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([NH:30][CH:31]([CH2:35][C:36]4[N:37]=[N:38][NH:39][N:40]=4)[C:32]([O-:34])=[O:33])=[O:21])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([NH:30][CH:31]([CH2:35][C:36]4[N:37]=[N:38][NH:39][N:40]=4)[C:32]([O-:34])=[O:33])=[O:20])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: CN1CCOCC1
Reactant: NC(Cc1nn[nH]n1)C(=O)O
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)NC(Cc3nn[nH]n3)C(=O)[O-])s1)C2
Product: [NH4+]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
After flame drying a 15 mL two-neck round bottom flask under argon, 0.18 g (0.57 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-thien-2-ylcarboxylic acid was suspended in 2 mL of anhydrous N,N-dimethylformamide, followed by the addition of 0.19 mL (1.7 mmol) of 4-methylmorpholine. After allowing the reaction mixture to stir at room temperature for 15 minutes, 0.15 g (0.86 mmol) of 2-chloro-4,6-dimethoxyl,3,5-triazine was added. The reaction was stirred at room temperature for 30 minutes, 0.135 g (0.86 mmol) of amino-3-(2H-tetrazol-5-yl)propanoic acid was added, and the reaction mixture was stirred at room temperature for an additional 3 hours. The volatiles were removed in vacuo, and the residue was treated with 50 mL of water and the solid was filtered and dried in a vacuum oven at 60° C. The crude solid was purified using rotary chromatography on a 2 mm Chromatotron® silica gel plate, and eluted with a gradient of 20% CH3OH/CHCl3 to 60:30:10 CHCl3 /CH3OH/NH4OH. The correct fractions were combined and concentrated in vacuo to give 0.050 g (18%) of 2-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)ethyl]thien-2-ylcarbonylamino}-3-(2H-tetrazol-5-yl)propanoic acid diammonium salt as a white solid. Rf 0.22 (5:3.5:1.5) (CHCl3 /CH3OH/NH4OH); m.p. 228° C. (foam); IR (KBr, cm-1)=553, 616, 746, 814, 1098, 1307, 1396, 1460, 1546, 1617, 3216; UV (0.1N NaOH) λmax =277, 217 (ε=19367, 19896); Exact Mass: Calcd=460.1515; Found=460.1508; 1H NM (300 MHz, DMSOd6) δ1.52-1.64 (m, 3H), 1.76-1.84 (m, 1H), 2.51-2.88 (m, 3H), 3.07-3.23 (m, 4H), 4.45-4.51 (m, 1H), 5.92 (s, 2H), 6.23 (s, 1H), 6.86 (d, J=3.1 Hz, 1H), 7.50 (d, J=3.4 Hz, 1H), 8.56 (d, J=7.3 Hz, 1H);
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1N
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Cl
Solvent: C1COCCO1
Product: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reaction time: 8 h

Procedure:
Impure 3-propanoyl-4-chloro-8-hydroxyquinoline (86 g) and 2-methylaniline (10.7 ml) in dioxan (200 ml) were warmed over a steam bath for 30 minutes, then left to stand overnight. After evaporation of the dioxan, dichloromethane and aqueous sodium bicarbonate were added, the organic layer washed with water and brine, dried and evaporated to a yellow solid. Recrystallisation from methanol gave 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (11.6 g), m.p. 125°-128°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([NH2:19])=[O:18])[CH2:15][CH:16]=3)=[CH:9][O:10][C:4]=2[C:3]=1[O:20][C@@H:21]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[Cl:31])[CH3:22].CCOC(C)=O>[Pd].CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([NH2:19])=[O:18])[CH2:15][CH2:16]3)=[CH:9][O:10][C:4]=2[C:3]=1[O:20][C@@H:21]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[Cl:31])[CH3:22]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(N)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](Oc1c(N)ncc2c(C3CCN(C(N)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-3-yl}-3,6-dihydro-2H-pyridine-1-carboxamide (17.0 mg, 0.037 mmol), palladium 10% wt on activated carbon (10 mg), EtOAc (4 mL) and MeOH (0.4 mL) was flushed with nitrogen, then a hydrogen (0.5 L) balloon was added, and the mixture was stirred at rt for 3 h. The suspension was filtered through a syringe filter pad, and the filtrate was concentrated in vacuo. The material was redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.55-1.69 (m, 2H), 1.87 (d, J=6.8 Hz, 3H), 1.98-2.06 (m, 2H), 2.89-3.03 (m, 3H), 4.11 (d, J=12.9 Hz, 2H), 6.53 (q, J=6.7 Hz, 1H), 7.18-7.25 (m, 1H), 7.37-7.43 (m, 2H), 8.02 (s, 1H). MS (ES+): m/z 467.01/469.00 (100/69) [MH+]. HPLC: tR=2.58 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1)#[N:15]>C(O)(C)C.CCCCCC>[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1)#[N:15]
Reactant: Fc1cccnc1N1CCNCC1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CCCCCC
Solvent: CC(C)O
Product: N#Cc1ccccc1OCC(O)CN1CCN(c2ncccc2F)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 1-(3-fluoro-2-pyridyl)piperazine (453 mg, 2.5 mmol) in 5 ml of isopropanol stirred at 70° C. under nitrogen was added portionwise 2-cyanophenoxy-2,3-epoxypropane (438 mg, 2.5 mmol) and the mixture stirred for 21/2 hours at 70° C. The solvent was removed in vacuo at room temperature and the residual oil was chromatographed on silica gel eluting with 5% methanol-chloroform. The product was obtained as a colorless oil which slowly solidified upon trituration in hexane to yield 0.66 g of 1-[3-(2-cyanophenoxy)-2-hydroxypropyl]-4-(3-fluoro-2-pyridyl)piperazine; m.p. 68°-70° C. Analysis satisfactory for C19H21FN4O2.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[F:13]>O.C(O)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[F:13]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Powered sodium cyanide (12.0 g, 0.24 mol) was dissolved in a 20 mL of water, and was added a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (60 g, 0.22 mol) in 30 mL of ethanol. After heating at reflux for 4 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was diluted with CH2Cl2, filtered, and concentrated to afford (4-bromo-3-fluorophenyl)acetonitrile, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=1.C(OCC)(=O)C>[C].[Pd].CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cn1
Yield: 93.7 %

Procedure:
A mixture of 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (13.4 g), palladium-carbon (5%, 1.5 g) and ethyl acetate (200 ml)-methanol (150 ml) was subjected catalytic hydrogenation at room temperature under one atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual crystals were collected by filtration to obtain 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (11.4 g, 93%). Recrystallization from ethyl acetate-hexane gave brown crystals, m.p.107.0-108.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[CH:9][C:10]2[CH:24]=[CH:23][C:13]([O:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2cccc(Cl)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(CNc2cccc(Cl)c2)cc1
Product: Cl
Reaction time: 1 h
Yield: 135 %

Procedure:
In 40 ml of methanol is dissolved 4.0 g of ethyl 2-[4-{N-(3-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate. Over a period of 1 hour, 0.44 g of sodium borohydride is added to the solution at 15° to 20° C. with cooling and stirring, and the mixture is stirred at the same temperature for 1 hour. After the reaction, the methanol is distilled off, and the residue is dissolved in ether. The solution is washed with water and dried. After drying, the ether is distilled off, and the resulting oily residue (3.8 g) is dissolved in 30 ml of ether. A mixture of hydrochloric acid and ethanol is added to the solution, and the resulting mixture is left to stand. The precipitated crystals are filtered off and washed with ether to give 3.0 g of ethyl 2-[4-(3-chloroanilinomethyl)phenoxy]-2-methylpropionate hydrochloride, mp 138° to 142° C. Recrystallization of the crystals from a mixture of ethanol and ether gives 1.6 g of crystals, mp 146° to 148° C.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[CH2:28]([OH:30])[CH3:29]>C(O)CO.C1(C)C=CC=CC=1>[CH2:28]1[O:30][C:5]2([NH:4][C:3]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14](=[O:15])[C:2]=3[N:1]=[CH:6]2)[O:7][CH2:29]1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: O=C1C2=C(NC3(C=N2)OCCO3)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (1.0 g, 5.05 mmol) in ethylene glycol (10 ml), toluene (20 ml) and p-toluenesulfonic acid (20 mg) was refluxed with water separation for 18 hours. The reaction mixture was cooled to room temperature, ethanol (5 ml) was added and the precipitate was filtered off and washed with ethanol and dried to give 1.014 g (83%) of the title compound. M.p. 296°-298° C. 1H-NMR (DMSO-d6, δ): 4.3-4.42 (m, 4H), 7.43-7.6 (m, 3H), 7.75 (d, 1H), 7.88 (s, 1H), 12.7 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH3:17])=O.C>N1C=CC=CC=1.CCOCC>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:17]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1nc2cccc(C)c2c(=O)o1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-amino-6-methyl benzoic acid (25g., 0.165 mol) in dry pyridine (125 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (47.33 ml, 3 equiv.) in a dropwise manner over 15 minutes. After stirring for 2 hours, the excess pyridine was removed under reduced pressure at a bath temperature of 40° C., and the residue was stirred vigorously in ice-cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml) and air-dried to give the crude product (30.4g). The crude product was treated with active charcoal (2g) in ether (200ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc/pet. ether gave 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one (28.1g, 83%) as colorless crystals; m.p. 104°-105° C.; analysis for C11H11NO3 : C, 64.38; H, 5.40; N, 6.83. Found: C, 64.21; H, 5.43; N, 6.80.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.[Si](C#N)(C)(C)C.[N:31]1([C:36](N2C=CN=C2)=[O:37])C=CN=[CH:32]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:12]=4)[CH2:32][NH:31][C:36]3=[O:37])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2cccc(-c3ccccc3)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (526 mg, 3.95 mmol), biphenyl-3-carbaldehyde (600 mg, 3.29 mmol), TMSCN (654 mg, 6.59 mmol), 10% PdC (100 mg), TEA (1.5 mL, 11 mmol), di-(imidazol-1-yl)methanone (475 mg, 1.03 mmol) as described in method 2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:24])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:22])[C@@H:17]([NH2:21])[CH2:18][CH2:19][CH3:20])=[N:12][CH:11]=1)[CH3:9].[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][C:26]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:2][O:3][C:4]([CH3:24])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:22])[C@@H:17]([NH:21][CH:31]2[CH2:32][CH2:33][C:34]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])=[N:12][CH:11]=1)[CH3:9].[OH:3][C:4]([CH3:24])([CH3:23])[CH2:5][CH2:6][CH2:7][CH:8]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:22])[C@@H:17]([NH:21][CH:31]2[CH2:32][CH2:33][C:34]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])=[N:12][CH:11]=1)[CH3:9]
Reactant: O=C1CCc2ccccc2C1
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)CCCC(C)(C)OC)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCC[C@H](NC1CCc2ccccc2C1)C(=O)Nc1ncc(C(C)CCCC(C)(C)O)s1
Product: CCC[C@H](NC1CCc2ccccc2C1)C(=O)Nc1ncc(C(C)CCCC(C)(C)OC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide HCl salt (600 mg, 1.59 mmol) and 2-tetralone (253 mg, 2.07 mmol) in dichloroethane was stirred at room temperature overnight. Sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water, adjusted pH to around 10 and extracted with methylene chloride. The organic layer was concentrated to dryness. The residue was purified by SCX column after eluting with 1 M NH3/methanol and concentrated to dryness to give 620 mg that was purified by Shimadzu HPLC to give 2-(S)-(1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(5-methoxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide, LC-MS RT=2.2 min, M+1=472.5 as an oil and 2-(S)-(1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(5-hydroxy-1,5-dimethyl-hexyl)-thiazol-2-yl]-amide, retention time, LC-MS RT=1.9 min, M+1=458.4 as a beige glass form.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=[CH2:2].C([Li])CCC.Br[CH2:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>C(OCC)C>[CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[C:4]=1[C:24]1([CH2:23][CH3:22])[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH2:2]
Reactant: C=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: BrCCC1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=Cc1ccc2c(c1C1(CC)c3ccccc3-c3ccccc31)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.15 g (6.0 mmol) 2-vinylfluorene in 100 mL diethyl ether was added 3.75 mL (6.0 mmol) n-butyllithium (1.6M in hexane). The reaction mixture was stirred for 4 hours at room temperature. Then 1.64 g (6.0 mmol) 1-bromo-2-(9-fluorenyl)ethane was added and the mixture was stirred for 14 hours at room temperature. The precipitate was removed by filtration, washed with methanol, filtered with pentane using silica gel 60, and concentrated by evaporation under vacuum. The yield was 1.69 g (73%) 1-(9-(2-vinyl)fluorenyl)-2-(9-fluorenyl)ethane as a colorless solid.