Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH:19]([CH3:21])[CH3:20])[C:3]1=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([NH:44][C@@H:45]([C:53](O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(OC(C)(C)C)=O>CN(C)C=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[NH2:44][C@H:45]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:53]([NH:1][CH:2]1[C:3](=[O:22])[N:4]([CH:19]([CH3:20])[CH3:21])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:54]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)N1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)C(NC(=O)[C@H](N)Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (+)-3-amino-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepine (40.8 g, 139 mmol) in dimethylformamide (140 mL) was added EDC (32.0 g, 167 mmol), HOBT (22.6 g, 167 mmol) and N-BOC-D-phenylalanine (44.3 g, 167 mmol). This was stirred at ambient temperature for 2 h. The reaction was diluted with saturated aqueous sodium hydrogen carbonate (1.5 L) and extracted with ethyl acetate (3×1 L). The organic layers were combined, dried with brine, anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil which was dissolved in ethyl acetate (700 mL), cooled in an ice/water bath. Hydrogen chloride gas was bubbled into the solution for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting foam was dissolved in ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate again (2×1 L). The organic layers were combined, dried with brine, anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a white solid, which was chromatographed over silica (2.5 kg) with ethyl acetate. The faster running diastereomer was recovered as a white solid (22.0 g, 72%). 1H NMR, CDCl3, δ 9.02 (d, J=8.6 Hz, 1H), 7.64-7.25 (m, 14H), 5.50 (d, J=8.6 Hz, 1H), 4.54 (septet, J=7.0 Hz, 1H), 3.70 (dd, J=3.9, 9.8 Hz, 1H), 3.34 (dd, J=3.9, 13.8 Hz, 1H), 2.82 (dd, J=9.8, 13.8 Hz, 1H), 1.51-1.40 (m, 5H), 1.27 (d, J=7.0 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[C:10]([C:9](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]([O:14][CH3:15])=[O:13])(=[O:11])[CH3:12]
Reactant: O=Cc1cccs1
Reactant: COC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1cccs1)C(C)=O
Yield: 94.8 %

Procedure:
A mixture of 112 g of 2-thiophenecarbaldehyde, 116 g of methyl acetoacetate, 770 ml of benzene, 4 ml of acetic acid and 3 ml of piperidine is heated under reflux for 2.5 hours under the condition of azeotropic dehydration. The benzene is evaporated under reduced pressure and the residual solvent is distilled off to give 199 g of methyl 2-acetyl-3-(2-thienyl)acrylate, boiling at 130°-160° C./0.2 mmHg.
Reaction SMILES: [H-].[Na+].C([N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=O)C.[CH:12](=O)[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>O1CCCC1.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[C:8]1[CH2:9][CH2:10][NH:6][C:7]1=[O:11]
Reactant: CC(=O)N1CCCC1=O
Reactant: COc1ccccc1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C=C1CCNC1=O
Yield: 11.8 %

Procedure:
Sodium hydride (16 g) was suspended in tetrahydrofuran (100 ml) and a solution of N-acetylpyrrolidone (25 g) and o-anisaldehyde (26.8 g) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling. After completion of the reaction, the reaction mixture was poured into water. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give oily 3-(2′-methoxybenzylidene)-2-pyrrolidone (4.7 g). The oil was dissolved in methylene chloride (60 ml). By demethylation using boron tribromide under ice-cooling, 3-(2′-hydroxybenzylidene)-2-pyrrolidone (4.0 g) was obtained as yellow crystals. To the crystals (1.5 g) were added dimethylformamide (50 ml) and potassium carbonate (2.2 g). (S)-Glycidyl nosylate (2.3 g) was added and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate to give an oily compound (1.8 g). By the reaction of the oil (0.5 g) and 4-(5,6,7,8-tetrahydronaphthalen-2-yl)piperidine (0.5 g) in methanol in the same manner as in Example 307, the title compound (0.4 g) was obtained, melting point 157–159° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:4])[CH:2]=[O:3].O.[N+:17]([C:20]1[CH:43]=[CH:42][CH:41]=[CH:40][C:21]=1[CH2:22][O:23][C:24]([NH:26][CH:27]([C@H:29]1[C@H:32]([CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[NH:31][C:30]1=[O:39])[CH3:28])=[O:25])([O-:19])=[O:18]>C1C=CC=CC=1>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][O:5][C:1]([CH:2]([OH:3])[N:31]1[C@@H:32]([CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:29]([CH:27]([NH:26][C:24]([O:23][CH2:22][C:21]2[CH:40]=[CH:41][CH:42]=[CH:43][C:20]=2[N+:17]([O-:19])=[O:18])=[O:25])[CH3:28])[C:30]1=[O:39])=[O:4])([O-:15])=[O:14]
Reactant: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)NC(=O)OCc1ccccc1[N+](=O)[O-]
Reactant: O=CC(=O)OCc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCC[C@H]1[C@H](C(C)NC(=O)OCc2ccccc2[N+](=O)[O-])C(=O)N1C(O)C(=O)OCc1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
Ortho-nitrobenzyl glyoxalate preferred from (0.650 g, 0.00153 mole) of di-o-nitrobenzyl tartarate, is dissolved in 20 ml benzene and refluxed using a Dean-Stark water separator containing CaH2 for an hour. Trans-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(2-acetoxyethyl)-2-azetidinone (0.580 g, 0.00153 mole) is added and the mixture is refluxed for 8 hrs, cooled, evaporated. The residue is column chromatographed ##STR210## to give 0.775 g (0.00132 mole, 87% yield) of the product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:21])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.ClCCl.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O1CCOCC1>[N:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]4[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=5)=[O:21])=[CH:15][CH:16]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:35][CH:34]=1
Reactant: O=C(CCCc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(CCCc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 102.5 °C
Yield: 59.4 %

Procedure:
Combine 4-[4-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-butyramide (0.15 g, 0.32 mmol), 4-pyridine boronic acid (0.04 g, 0.35 mmol), S-Phos (0.02 g, 0.04 mmol) and K3PO4 (0.13 g, 0.63 mmol) with dioxane (3.5 mL) and water (1.5 mL) and stir at room temperature while the reaction contents are de-gassed with nitrogen for 5 minutes. Add palladium diacetate (0.01 g, 0.04 mmol). Heat to 100-105° C. for 20 hours. Cool and dilute with water (10 mL) and dichloromethane. The organic layer are then filtered onto a pre-equilibrated in methanol Varian SCX column (10 g), washed with 30 mL each of water, methanol, dichloromethane and methanol. Elute crude product with 2N methanolic ammonia (50 mL). Concentrate the ammonia solution in vacuo to dryness to yield a residue that is chromatographed on silica (0→3% methanol in ethyl acetate over 30 min) to yield 4-[4-(7-Pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-butyramide (0.10 g, 0.19 mmol). MS(ESI), m/z 501 (M+1).
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:74])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[C:48]([C:70]([F:73])([F:72])[F:71])[CH:47]=2)[CH:39]=[CH:40][C:41]=1[F:42]>>[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:74])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[C:48]([C:70]([F:73])([F:71])[F:72])[CH:47]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3C(F)(F)F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3C(F)(F)F)cc2C1=O
Yield: 87 %

Procedure:
The compound of example 418 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 417.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:32]=C)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:35].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:32]=[O:35])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnc2c1nc(C=O)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.6 %

Procedure:
In a mixed solution of 4 mL of tetrahydrofuran and 1 mL of water, 20 mg (0.04 mmol) of 1-[4-(6-amino-8-vinyl-purin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-urea was dissolved, and 20 μL of a 0.1 M osmium tetraoxide aqueous solution and 40 mg (0.19 mmol) of sodium periodate were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 18 mg (90%) of a target product as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1.CO>[C:36]([N:25]1[CH2:24][CH:23]([C:16]2[C:15]([O:27][CH3:28])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:21]=[C:20]([Cl:22])[C:17]=2[C:18]#[N:19])[CH2:26]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)=O)C1
Temperature: 20 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (60 mg, 0.15 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with triethylamine (53 μL, 0.38 mmol) followed by acetyl chloride (13 μL, 0.18 mmol) and stirred at 20° C. overnight. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (39 mg, 59%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.36 (br s, 2H), 6.26 (q, J=7.0 Hz, 1H), 4.57-4.36 (m, 3H), 4.30-4.21 (m, 1H), 4.18-4.08 (m, 1H), 3.71 (d, J=3.1 Hz, 3H), 2.55 (s, 3H), 1.78-1.71 (m, 6H). LCMS for C21H23ClN7O2 (M+H)+: m/z=440.2; Found: 440.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[N:30][CH:31]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH:24][C:26]4[CH:31]=[N:30][C:29]([N:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[CH:28][CH:27]=4)[N:23]=3)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(C(F)(F)F)cn4n3)cn2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(5-bromo-pyridin-2-yl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (16% yield). MP 210-215° C. 1H NMR (400 MHz, (CDCl3, δ, ppm): 8.79 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=8.5 Hz, 2H), 8.14 (d, J=7.3 Hz, 2H), 7.90 (d, 1H), 7.80 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 6.96 (d, 1H), 6.88 (s, 1H), 3.21 (bm, 4H), 3.13 (s, 3H), 2.66 (bm, 4H), 1.57 (s, 3H). MS=532.1 (MH)+.
Reaction SMILES: [NH2-].[Na+].C([O:10][C:11](=O)[C@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[CH3:55][S:56]([CH3:58])=[O:57]>O1CCCC1>[CH2:14]([N:13]([C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:11](=[O:10])[CH2:55][S:56]([CH3:58])=[O:57])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CS(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
3.76 g (96.39 mmol) of sodium amide was suspended in 40 ml of dimethylsulfoxide and heated at from 74° to 75° C. for 30 minutes. 40 ml of tetrahydrofuran was added to the resulting solution and cooled to 0° C. To this was dropwise added a solution of 15.47 g (90.5 wt. %, 32.14 mmol) of N,N-dibenzyl-(L)-phenylalanine benzyl ester as dissolved in 20 ml of tetrahydrofuran, while keeping it at 0° C. After these were reacted at 0° C. for 30 minutes, 120 ml of an aqueous solution of 10% citric acid and 100 ml of ethyl acetate were added to the reaction mixture, which was thus subjected to phase separation. The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate, and the resulting extract was combined with the previously-separated organic layer and then washed with 60 ml of a saturated saline solution. This was dried with anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) and then crystallized in toluene/hexane to obtain 11.16 g of the above-entitled compound. The yield was 85.6%. The integral ratio in 1H-NMR of the compound verified that the ratio of the diastereomers constituting it is about 1:1.
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][CH:16]=1)([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[CH3:3]>C(Cl)Cl>[CH3:6][C:7]1([CH3:8])[O:10][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([C:4]2[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=2)([CH3:1])[CH2:3]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: ClCCl
Product: CC1(C)CC(C)(c2ccc(O)cc2)c2ccccc2O1

Procedure:
To a 4-necked, round bottom flask equipped with a mechanical stirrer, water cooled condenser, dropping funnel, and heated by means of electrical tape, there was placed 500 grams of methylene chloride. To the well stirred methylene chloride solution, there was added the 500 grams of molten BPA by-products, the rate of addition of the molten by-products being used to control the reflux rate of the methylene chloride. The temperature of the solvent was 40° C. and had a dark color. After the addition of about half of the molten by-products, yellow colored crystals formed in the solution. Upon completing the addition of the molten by-products, the resultant thick, yellow mixture was cooled and filtered. The filter cake was washed with fresh methylene chloride to afford a white solid. The white, chroman-I concentrate filter cake was dried at 100° C. for 24 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][O:9]1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: Fc1ccccc1C1CO1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2ccccc2F)cc1
Temperature: 78 °C
Yield: 11 %

Procedure:
To a stirring solution of 2-(2-fluorophenyl)oxirane (5.30 g, 38.4 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.0 g, 58.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction was allowed to cool to RT and then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed, eluting with 30-40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.10 g (11%) of the title compound as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.67 g (7%) of the regioisomer as a colorless oil.
Reaction SMILES: [CH2:1]([C:11]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1)[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].I[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH:1]([C:2]1[N:6]([CH2:5][CH2:4][CH3:10])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)([C:11]1[N:12]([CH2:2][CH2:1][CH3:11])[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: c1ccc2[nH]c(Cc3nc4ccccc4[nH]3)nc2c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1nc2ccccc2n1CCC)c1nc2ccccc2n1CCC
Reaction time: 0.33 h
Yield: 151 %

Procedure:
To a flask were added 0.79 g 2,2′-methylenebis(1H-benzimidazole) and 20 ml N,N-dimethylformamide under nitrogen. 0.42 g sodium hydride were added in portions and the mixture was stirred 20 minutes. 1.74 g 1-iodopropane were added slowly and the mixture was stirred at 22 C for 16 hrs. After quenching with the slow addition of 40 ml water, the product was extracted with ethyl acetate and washed with water. Solvent removal resulted in an oil which was purified by silica gel chromatography using 25% ethyl acetate in hexane to give 0.9 g of a light yellow oil which crystallized on standing.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.C(O)C.[H][H]>C(Cl)Cl.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCCCCCBr)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(OCCCCCCCCBr)cc1

Procedure:
Into a glass hydrogenation vessel were added 1-(8-bromooctyloxy)-4-nitrobenzene (5.00 g, 15.1 mmol) and absolute ethanol (50 mL). Carefully, 10% Pd/C (0.5 g) was added, the vessel was charged with hydrogen (40 psi), and the mixture was shaken on a Pan hydrogenation apparatus. After 3 h the mixture was diluted with CH2Cl2 (25 mL), filtered through a Celite pad, and volatiles removed in vacuo to give 4.20 g (14.0 mmol, 93%), of as a pale pink solid, mp 61-63° C. This material was used without purification in the next reaction. 1H NMR (500 MHz, CDCl3) δ 1.27-1.44 (m, 8H), 1.75-1.84 (m, 4H), 3.39 (t, J=5.0 Hz, 2H), 3.89 (t, J=6.5 Hz, 2H), 6.77-6.88 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 22.7, 25.9, 26.0, 28.1, 28.7, 29.2, 29.4, 31.8, 32.8, 34.0, 68.5, 115.7, 118.6, 135.2, 154.1; HRMS (ESI) calculated for C14H23BrNO [M+H]+ 300.0957, observed 300.0963.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C)n1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 98.7 %

Procedure:
To a solution of methyl 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (1.50 g, 3.88 mmol) in tetrahydrofuran (15.0 mL) was added lithium tetrahydroborate (337.8 mg, 15.51 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 6.5 hrs. After cooling, the reaction mixture was quenched with aqueous saturated ammonium chloride at 0° C. The solvent was concentrated and the precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (1.38 g, 3.83 mmol, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])=[O:5])[CH3:2].[Cl-].[CH3:15][NH2+]C.C=O>>[CH:12]([C:11](=[CH2:15])[CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:13]
Reactant: C[NH2+]C
Reactant: CCOC(=O)COCCCCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCCOCC(=O)OCC

Procedure:
16 g (85 mmol) of 5-ethoxycarbonylmethoxypentanal, 7.8 g (95.2 mmol) of dimethylammonium chloride and 7.4 ml (99.4 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The reaction mixture is allowed to cool and extracted three times with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and concentrated by evaporation giving ethyl 7-formyl-3-oxaoct-7-enoate as a colourless oil which is further reacted without purification.