Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:15]([NH:19][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Cl:5])=[N:7][CH:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
25.7 ml (349 mMol) Thionylchloride and 0.5 ml (6.35 mMol) DMF were added to a suspension of 50.0 g (317 mMol) 6-chloro-nicotinic acid in 250 ml toluene and the reaction mixture was heated to 80° C. for 2 hours. After cooling to 10° C., 100.5 ml (952 mMol) tert.-butylamine were added over 40 minutes and stirring was pursued for 30 minutes at the same temperature. 250 ml Aqueous sodium hydroxide 2N were added and the mixture was stirred 30 minutes at room temperature. Dilution with 300 ml water and extraction with ethyl acetate yielded 63.3 g (94%) N-tert.-butyl-6-chloro-nicotinamide as a beige powder of m.p.=108-110° C.
Reaction SMILES: C[C:2]1[N:3]=CN[C:6]=1[CH2:7]SCCN.C(C=C(OC)OC)#N.[C:20]([CH:22]=[C:23](OC)[NH:24][CH2:25][CH2:26][S:27][CH2:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[CH3:34])#[N:21].C(N)C#C>>[C:20]([CH:22]=[C:23]([NH:3][CH2:2][C:6]#[CH:7])[NH:24][CH2:25][CH2:26][S:27][CH2:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[CH3:34])#[N:21]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: COC(=CC#N)NCCSCc1[nH]cnc1C
Agent: C#CCN
Agent: COC(=CC#N)OC
Product: C#CCNC(=CC#N)NCCSCc1[nH]cnc1C

Procedure:
When 2-[(4-methyl-1H-imidazol-5-yl)methylthio] ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene according to the procedure of Example 6, Step A, and the resultant 1-cyano-2-methoxy-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene is treated with propargylamine by the procedure of Example 6, Step B, the title compound is produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc2cc(Br)ccc2c1
Temperature: 65 °C

Procedure:
A mixture of 5 g of 6-bromo-2-naphthol, 50 ml of dimethyl sulfoxide, 3.9 ml of 6-bromoheptane, 7.1 g of potassium iodide and 7.1 g of milled potassium carbonate activated at 80° C. in high vacuum is heated to 65° C. for 16 hours. It is then cooled and is partitioned between ethyl acetate and water and the organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 200 g of silica gel using toluene and subsequent crystallization from toluene/hexane (8:1) give 6-bromo-2-heptyloxynaphthalene.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([CH:28]1[N:33]2[CH2:34][C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:36][C@H:32]2[CH2:31][NH:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:52]([N:55]2[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]2)=[CH:51][C:48]=1[CH:49]=O>ClCCl>[CH:15]([C@H:28]1[N:33]2[CH2:34][C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:36][C@H:32]2[CH2:31][N:30]([CH2:49][C:48]2[CH:51]=[C:52]([N:55]3[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]3)[CH:53]=[CH:54][C:47]=2[O:46][CH3:45])[CH2:29]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNCC(C(c3ccccc3)c3ccccc3)N2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
Sodium triacetoxyborohydride (163 mg) was added to a mixture of bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (0.38 g) and 2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzaldehyde (210 mg) in dichloromethane, and the whole was stirred for 3 hours at room temperature. The mixture was washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The later eluting fractions were collected and evaporated under reduced pressure to give colorless oil of (4R,7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-octahydropyrrolo[1,2-a]pyrazine (0.18 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11][S:12][CH:13]([F:15])[F:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([O:18][CH3:21])=[O:17])[CH2:10][CH2:11][S:12][CH:13]([F:14])[F:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSC(F)F)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC(F)F)NC(=O)OC(C)(C)C

Procedure:
To a solution of N-tert-butoxycarbonyl-S-difluoromethylhomocysteine in diethyl ether (1 mL) was added a solution of diazomethane in ether until a faint yellow color persisted. The excess reagent was quenched by addition of glacial acetic acid, and the reaction was concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to afford a colorless oil (400 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([C:16]1[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[F:34])[N:27]([CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C)[C:26](=[O:45])[CH2:25]2)=[O:23])=[C:18]([CH3:48])[CH:17]=1)=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([C:16]1[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[F:34])[N:27]([CH2:35][CH2:36][OH:37])[C:26](=[O:45])[CH2:25]2)=[O:23])=[C:18]([CH3:48])[CH:17]=1)=[O:15]
Reactant: Cc1cc(C(=O)NCc2ccccc2-c2ccco2)ccc1CNC(=O)N1CC(=O)N(CCO[Si](C)(C)C(C)(C)C)c2cccc(F)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2ccccc2-c2ccco2)ccc1CNC(=O)N1CC(=O)N(CCO)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[2-(tert-butyldimethylsilanyloxy)ethyl]-8-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 4-[(2-furan-2-ylphenyl)methylcarbamoyl]-2-methylbenzylamide from Example 21F (0.34 mmol) in THF (5.0 ml) was added a solution of tetrabutylammonium fluoride in THF (1.0 M, 1.0 ml, 1.0 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 3 days. The mixture was evaporated in vacuo and the residue was taken up in CH2Cl2 and washed with ammonium chloride solution. The organic phase was dried and evaporated in vacuo and the residue was purified by flash chromatography on silica (eluant CHCl3:methanol 95:5) to give a white solid; yield 120 mg, 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]2[CH:33]=[CH:34][O:35][C:31]=2[CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[C:31]2[CH:30]=[C:29]([CH2:28][NH:27][C:3]3[C:4]4[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=4[CH:17]=[CH:18][C:2]=3[Cl:1])[CH:37]=[CH:36][C:32]=2[CH:33]=[CH:34]1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc2ccoc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc4ccoc4c3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.35 mmol) and 6-aminomethyl-benzofuran (0.2 g, 1.06 mmol) with tris(dibenzylideneacetone)dipalladium (0) (32.0 mg, 0.04 mmol), BINAP (88.0 mg, 0.11 mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90° C. for 17 h, to obtain 6-[(benzofuran-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[C:36]([C:50]([F:53])([F:52])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[C:36]([C:50]([F:53])([F:51])[F:52])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:54]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(C(F)(F)F)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) was dissolved in ethanol (100 ml), and to the solution, sodium borohydride (0.15 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 16) (0.63 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([NH:14][C@H:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH3:16])=[O:13])=[CH:5][CH:4]=1.O[Li].O>>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:11][CH2:10][CH:9]2[C:12]([NH:14][C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH3:16])=[O:13])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CCN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1CCN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 29.6 %

Procedure:
The title compound (E36) (2 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1S)-1-(1-(4-(trifluoromethyl)benzyl)azetidine-2-carboxamido)ethyl)benzoate (diastereoisomer 2) (D152b) (7 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH:15]([P:24]([O:29]CC)(=[O:28])[O:25]CC)[P:16]([O:21]CC)(=[O:20])[O:17]CC)[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.C[Si](Br)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH:15]([P:16]([OH:21])(=[O:17])[OH:20])[P:24]([OH:29])(=[O:25])[OH:28])[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOP(=O)(OCC)C(Cc1cc(OC)c(O)c2ccccc12)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Product: COc1cc(CC(P(=O)(O)O)P(=O)(O)O)c2ccccc2c1O
Yield: 67 %

Procedure:
Following the same method as described in Example 2, 7.12 g (15 mmol) of the tetraethyl 2-[3-methoxy-4-hydroxy-1-naphthyl]ethane-1,1-diphosphonate obtained in Example 11 was treated with trimethylsilyl bromide, and then hydrolysis was effected to obtain 3.64 g of the title compound as pale yellow crystals. The yield was m.p.: 231°-232° C. (dec)
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(Cl)(=O)C(Cl)=O.O[C:27]1[CH:62]=[CH:61][C:30]([CH2:31][N:32]([CH2:53][C:54]([O:56]C(C)(C)C)=[O:55])[C:33](=[O:52])[C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:51])[CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)=[CH:36][CH:35]=2)=[CH:29][CH:28]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][C:41]([NH:40][C:37]2[CH:36]=[CH:35][C:34]([C:33]([N:32]([CH2:53][C:54]([OH:56])=[O:55])[CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:16][C:15](=[O:17])[C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:19][CH:18]=4)=[CH:62][CH:61]=3)=[O:52])=[CH:39][CH:38]=2)=[O:51])=[CH:48][CH:47]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(nonyloxy)benzoic acid (31 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 30 min. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 2 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 6.6 mg (12%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-(nonyloxy)benzoyl)oxy)benzyl)benzamido) acetic acid 16. LCMS-ESI (m/z) calculated for C41H46N2O8: 695; found 694 [M−H]−, tR=10.43 min (Method 4). 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.47-7.27 (m, 4H), 7.23 (d, J=8.0 Hz, 4H), 7.10 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.62 (d, J=35.9 Hz, 2H), 4.07 (t, J=6.5 Hz, 2H), 3.92 (d, J=40.2 Hz, 2H), 3.71 (s, 3H), 3.56 (s, 2H), 1.85-1.66 (m, 2H), 1.53-1.10 (m, 12H), 0.85 (t, J=6.7 Hz, 3H).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>C(Cl)(Cl)Cl>[C:6]([CH:14]([NH2:13])[CH2:15][O:16][CH2:17][CH2:18][OH:19])([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12]
Reactant: NCCOCCO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(N)COCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
A solution of di-tert-butylcarbonate (10.27 g, 47.2 mmol) in chloroform (40 mL) was added to a solution of 2-(2-aminoethoxy)-ethanol (5.0 g, 47.62 mmol) in chloroform (40 mL) and the mixture was stirred at room temperature for 1.5 hrs. The solution was washed with water (30 mL), the organic layer dried (MgSO4), and concentrated in vacuo to give 2-(2-Boc-aminoethoxy)-ethanol (9.6 g, 99%). 1H NMR (300 MHz, CDCl3) δ 5.43 (s, 1H), 3.43 (s, 1H), 3.56 (m, 4H), 3.73 (t, 2H, J=5.4 Hz), 3.32 (m, 2H), 1.45 (s, 9H); 13C NMR (67.8 MHz, CDCl3) δ 156.06, 79.06, 77.18, 72.14, 70.08, 61.31, 40.21, 28.21.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@@H:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18]C)[C@H:4]([OH:20])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].B(F)(F)F.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C>[OH:18][C:9]1[C:8]([C@@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[OH:20])=[C:13]([O:14][CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(OC)c1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(O)c1C(C)=O
Temperature: 0 °C

Procedure:
Compound of example 2 (15 g, 53.4 mmol) was reacted with acetic anhydride (27.2 g, 269 mmol) in the presence of BF3-etherate (37.9 g, 267 mmol) at 25° C. The reaction mixture was poured over crushed ice, made basic using saturated Na2CO3 solution. It was extracted using CHCl3 (3×200 mL). The organic extract was washed with water, dried (anhydrous Na2SO4), and concentrated. The solid obtained was treated with 5% aqueous NaOH (85 mL) at 55-60° C. for 1 h. It was diluted with ice water (100 mL), acidified with acetic acid (pH 5), and further basified using aqueous Na2CO3 (pH 9). Filtration afforded the compound which was washed with water and dried to get the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:18].C(=O)([O-])O.[Na+].O>ClCCl>[Br:18][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1CBr
Temperature: 5 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
1.3 g of tert-butyl (2-hydroxymethylphenyl)carbamate were dissolved in 20 ml of dichloromethane; at 5° C., a solution of 630 mg of phosphorus tribromide in 5 ml of DCM was then added dropwise. The reaction mixture was subsequently stirred at 5° C. for 2 h. For workup, the mixture was admixed cautiously with solid sodium hydrogencarbonate and 1 ml of water, stirred at 5° C. for 30 min, filtered through a cartridge and concentrated under reduced pressure. tert-Butyl (2-bromomethylphenyl)carbamate was obtained in a 67% yield. 1H NMR: 8.71, s, 1H, 7.45, d, 1H, 7.42, d, 1H, 7.3, t, 1H, 7.1, t, 1H; 4.78, 2, 2H, 1.45, s, 9H.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[N:17]1([CH2:16][CH2:15][O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c2ccccc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A mixture of 4-[2-(4-nitro-naphthalen-1-yloxy)-ethyl]-morpholine (10 g, 33.0 mmol), MeOH (80 ml) and Pd/C (10%, 1.0 g) is shaken under a hydrogen atmosphere at 30 psi for 4 hours. The mixture is then filtered through a bed of Celite under a stream of nitrogen. The filtrate is reduced under vacuum to give 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (7.32 g, 81.3%). 1H NMR (300 MHz, CDCl3) δ 8.21 (m, 1H), 7.81 (m, 1H), 7.49 (m, 2H), 6.69 (s, 2H), 4.23 (t, 2 H), 3.76 (t, 4H), 2.92 (t, 2H), 2.65 (t, 4H). MS: 273 (M+1).
Reaction SMILES: [CH:1]([Si:3]([CH:6]=[CH2:7])(Cl)Cl)=[CH2:2].[CH3:8][C:9]([CH3:12])([O-:11])[CH3:10].[K+].[Cl-].[K+]>CCCCCC>[CH:1]([Si:3]([CH:6]=[CH2:7])([O:11][C:9]([CH3:12])([CH3:10])[CH3:8])[O:11][C:9]([CH3:12])([CH3:10])[CH3:8])=[CH2:2]
Reactant: CC(C)(C)[O-]
Reactant: C=C[Si](Cl)(Cl)C=C
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Product: C=C[Si](C=C)(OC(C)(C)C)OC(C)(C)C
Reaction time: 17 h
Yield: 56.5 %

Procedure:
306 g (2.00 mol) of divinyldichlorosilane, 539 g (4.80 mol) of potassium tert-butoxide and 3.0 L of dry hexane were charged in a 5 L four-necked flask equipped with a dropping funnel and a mechanical stirrer in a stream of nitrogen, and reaction was carried out for 17 hours under reflux with hexane. After completion of the reaction, potassium chloride residue as a by-product was removed by filtration, and the obtained filtrate was distilled under reduced pressure to obtain 257 g (1.13 mol) of divinyl di-tert-butoxysilane as an aimed product. The yield was 56.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH2:27][CH:28]=[CH2:29]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:29][CH2:28][CH:27]=[CH2:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: C=CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (150 mg, 0.380 mmol) in tetrahydrofuran (3.8 mL) was added dropwise 3-butenylmagnesium bromide (ca. 0.8 M solution in diethyl ether, 0.900 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:22][C:23]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:24]=1C(OC)=O>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:24]2[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:23]=2[F:22])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1cc(C(F)(F)F)ccc1F
Reaction time: 0.08 h

Procedure:
A solution of 4-chlorophenylacetic acid (2.074 g, 12.15 mmol) in THF (16 mL) was added drop wise over three minutes to NaHMDS (1.0 M in THF, 33 mL, 33 mmol) at −78° C., then the solution was stirred for five minutes. A solution of methyl 2-fluoro-5-(trifluoromethyl)benzoate (1.93 ml, 12.2 mmol) in THF (16 mL) was added in portions over five minutes, then the solution was stirred at −78° C. for five hours. The solution was diluted with 2 N HCl (aq, 300 mL) then extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-50% DCM/hexanes to afford the title compound as a yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.15 (dd, J=6.5, 2.3 Hz, 1H); 7.81-7.77 (m, 1H); 7.31-7.24 (m, 3H); 7.17 (d, J=8.2 Hz, 2H); 4.27 (d, J=2.7 Hz, 2H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH3:13]>CCOCC>[CH2:7]([O:6][C:1](=[O:5])[CH:2]([O:3][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:4])[CH3:8]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCCI
Solvent: CCOCC
Product: CCCCOC(C)C(=O)OCC
Reaction time: 15 h
Yield: 49.5 %

Procedure:
31.5 g of ethyl L-(+)-lactate and 107.3 g of 1-iodobutane were mixed into a four-necked flask, and freshly synthesized Ag2O was added in 2 hours. After left standing at room temperature for 15 hours, the mixture was diluted with 200 ml of ether, filtered and then ether was evaporated. The residue was washed with 100 ml of an aqueous 5% KOH, dried over anhydrous Na2SO4 and subjected to vacuum distillation. The fractions at 110° C./54 mmHg were collected to give 23 g of (-)-ethyl-2-butoxypropionate.