Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>O1CCOCC1.O>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:39])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (500 mg, 2.171 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1200 mg, 8.69 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (562 mg, 2.171 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and then treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water with 0.1% TFA buffer) to afford the product (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (294 mg, 30% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.83 (t, J=6.6 Hz, 2H), 7.68-7.58 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.30 (m, 2H), 4.65 (br. s., 1H), 4.58 (d, J=13.7 Hz, 1H), 4.55-4.39 (m, 3H), 4.33-4.18 (m, 1H), 2.91-2.85 (m, 4H), 1.47 (s, 9H). ESI-MS(+) m/z=475 (M+Na).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:3]1([CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[Si:11]([Cl:13])([Cl:12])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:2][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(Cl)c1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)C(c1ccccc1)c1ccccc1
Yield: 43.8 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.14 g (0.47 mmol) of tetrabutylphosphonium chloride, 0.95 g (4.69 mmol) of 1-chloroethylbenzene, and 1.91 g (14.10 mmol) of trichlorosilane were reacted at 150° C. for 6 hrs. The resulting mixture was distilled to give 0.31 g diphenyl-1-trichlorosilylmethane (yield; 22%).
Reaction SMILES: [N+:1]([C:4]1[CH:76]=[CH:75][C:7]([CH2:8][CH:9]2[CH2:26][N:25]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23][N:22]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:21][CH2:20][N:19]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:18][CH2:17][N:16]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:15][CH2:14][N:13]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:12][CH2:11][N:10]2[CH2:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:76]=[CH:75][C:7]([CH2:8][CH:9]2[CH2:26][N:25]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23][N:22]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:21][CH2:20][N:19]([CH2:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:18][CH2:17][N:16]([CH2:51][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:15][CH2:14][N:13]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:12][CH2:11][N:10]2[CH2:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)C(Cc2ccc([N+](=O)[O-])cc2)CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)C(Cc2ccc(N)cc2)CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Yield: 62 %

Procedure:
To a solution of 2-(4-nitrobenzyl)-1,4,7,10,13,16-hexakis(tert-butoxycarbonylmethyl) -1,4,7,10,13,16-hexaazacycloocta (6) (15 mmol) in ethanol (50 ml) at room temperature under a nitrogen atmosphere was added SnCl2 (0.125 mol). The mixture was refluxed for 12 hours after which the solvent was removed and the compound thus obtained was dissolved in water; the solution was brought to pH 8 with 2M NaOH. The resulting precipitate was removed off and the filtrate concentrated on vacuum; the residue was dissolved in acetonitrile and passed over Celite. The filtrate was evaporated on vacuum to give yellow oil. The yield was 62%.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:34]([O:36][C:37](Cl)=[O:38])[CH3:35].C(N(CC)CC)C>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:38])[N:29]=[C:27]([NH2:28])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17](=[O:18])[CH:16]([C:12]2[C:13]([F:15])=[CH:14][C:9]([C:6]3[CH:7]=[N:8][C:3]([NH2:2])=[CH:4][CH:5]=3)=[CH:10][C:11]=2[F:33])[O:30][CH2:31][CH3:32])=[CH:22][CH:23]=1)[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N=C(N)c1ccc(CNC(=O)C(OCC)c2c(F)cc(-c3ccc(N)nc3)cc2F)cc1

Procedure:
Analogous to example 15.4, (RS)-(2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-carbamimidoyl-benzyl)-2-ethoxy-acetamide hydrochloride (example 271) was reacted with ethylchloroformate and triethylamine in DMF to give (RS)-[amino-[4-({2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-2-ethoxy-acetylamino]-methyl)-phenyl]-methylene}-carbamic acid ethyl ester. Off-white solid. MS 512.1 ([M+H]+)
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.B>O1CCCC1.CO>[N:6]1([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH2:14][OH:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1ccccc1N1CCNCC1
Agent: B
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazin-1-yl-benzoic acid sulfuric acid salt (˜10 mmol) was suspended in 50 mL of tetrahydrofuran. Then 100 mL of 1.0 M borane in tetrahydrofuran (100 mmol) was added and the reaction was stirred at room temperature overnight with a bubbler attached to release pressure in the flask. The reaction mixture was diluted with 50 mL of methanol. The reduced product (470 mg) crystallized out of the mixture during evaporation.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:27])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:18]([O:20]C)=[O:19])[N:10]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:27])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:18]([OH:20])=[O:19])[N:10]=1
Reactant: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Oc4ccc(F)cc4F)ccc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-[2-(2,4-difluorophenoxy)-6-oxo-6H-pyrido[1,2-b]pyridazin-5-yl]-4-methoxybenzoate (750 mg) dissolved in dioxane (10 mL) was added 1 N NaOH (10 mL). The reaction stirred at room temperature for 3 hrs until completion by LCMS analysis. The reaction was diluted with H2O, washed with ether, and acidified to pH 4.5. The solid precipitate was collected and dried to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[O:15]=[C:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1>O1CCCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: OCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2CO)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
A solution of (2-bromophenyl)methanol (56 g) in tetrahydrofuran (300 mL) was cooled to −78° C., n-butyllithium (1.6 M, hexane solution, 390 mL) was slowly added dropwise. After stirring at −78° C. for 1 hr, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (60 g) in tetrahydrofuran (200 mL) was added dropwise. The reaction mixture was warmed to room temperature, and the mixture was stirred at room temperature overnight. The reaction was quenched with water and stirring at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 40%-80%) and crystallized from ethyl acetate-hexane to give the object product (35 g).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[F:51][C:52]([F:56])([F:55])[CH2:53][NH2:54]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:54][CH2:53][C:52]([F:56])([F:55])[F:51])=[O:24])[C:10]1=[O:11]
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@@H](CC(C)C)N(C(=O)[C@H](NC(=O)OC(C)(C)C)C1Cc2ccccc2C1)[C@@H](C(=O)O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NCC(F)(F)F)c1ccc(F)cc1
Reaction time: 0.03 h

Procedure:
A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μl), phosphorusI (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol:dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.[Br-].[Na+].[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
40 mg of L-Nα -[(2S)-3-isopropylthio-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine methyl ester was dissolved in 0.6 ml of dioxane. 0.3 ml of a 37 mg/ml sodium bromide trihydrate aqueous solution was added thereto at room temperature. The reaction solution was stirred at room temperature for 15 minutes, and then diluted with 20 ml of ethyl acetate. The reaction solution was washed with 8 ml of water and then with 8 ml of a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure to obtain yellow solid. This product was saponified with a solution of 0.4N potassium hydroxide in methanol/water (10/1) to obtain 40 mg of L-Nα -[(2S)-3-isopropylsulfinyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine (Rf: 0.48, chloroform/methanol/33% acetic acid=10/1/0.2). This compound was condensed in the same manner as in Example 11 with (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol by a usual DPPA method, further subjected to removal of a triphenylmethyl group by dichloromethane/TFA (3/4). The product was purified by silica gel column chromatography (chloroform/methanol/conc. aqueous ammonia=30/3/0.02) to obtain 20 mg of (2S,3R,4S)-4-{L-Nα -[(2S)-3-isopropylsulfinyl-2-(1-naphthylmethyl)propionyl]histidyl}amino-5-cyclohexyl-i-morpholino-2,3-pentanediol as white solid.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2>C(Cl)Cl>[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:19])[C:16]([NH:2][CH3:1])=[O:17])=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)C(C)c1ccc2c(c1)CCc1ccccc1C2=O

Procedure:
A 2.6N solution of methylamine in methylene chloride (250 cc.) is added at 0°C. and over the course of 30 minutes to a solution of 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (10 g.) in methylene chloride (100 cc.). The reaction mixture is concentrated, and the residue taken up in distilled water (100 cc.) and benzene (300 cc.). The organic layer is decanted, dried over anhydrous sodium sulphate and evaporated at 60°C. under reduced pressure (20 mm.Hg). The product obtained is recrystallised from di-isopropyl ether (100 cc.) to give 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)-N-methylpropionamide (5.8 g.) melting at 140°C.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[K+]>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Yield: 99.1 %

Procedure:
3-(2′,4′-Difluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (4.2 g, 11.86 mmol) and 2N KOH (23.72 mL, 47.45 mmol) in 210 mL MeOH were refluxed for 1 hr. The reaction mixture was cooled, concentrated and distributed into 200 mL H2O and 200 mL ethyl acetate. The aqueous layer was acidified with 2N HCl and separated. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to yield 4.0 g (99.1%) of 3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-benzoic acid as a white powder. LC-MS (ES) calculated for C20H14F2O3, 340.33; found m/z 339.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1.[Cl:22]N1C(=O)CCC1=O>C1COCC1>[Cl:22][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)[C:5]=1[CH3:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c[nH]c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: Cc1[nH]c(Cl)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (80 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to −60° C. N-Chlorosuccinimide (41 mg, 0.31 mmol) was dissolved in THF (2 mL) and added dropwise, keeping the internal temperature ≦−50° C. The mixture was stirred for 30 min with cooling then evaporated in vacuo. The residue was treated with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The crude product was purified by SiO2 chromatography (heptane/EtOAc gradient elution) to afford the title compound (37 mg) as an orange solid after recrystallisation from iPr2O. M.p. 200–203° C. MS: [M+H]+=317.7 (C16H14ClFN4 requires 316.8). 1H-NMR (CDCl3) δ: 2.17 (s, 3H, CH3), 2.42 (s, 3H, CH3) 6.77 (d, 1H, J=5.9 Hz, pyrimidinyl-H), 7.02–7.06 (m, 3H, Ph-h, NH), 7.54–7.56 (m, 2H, Ph-H), 7.95 (br. s, 1H, NH), 8.25 (d, 1H, J=5.4 Hz, pyrimidinyl-H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH3:12].[CH2:14]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])Cl)[CH3:15]>C(N(CC)CC)C>[CH2:1]([O:13][Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH3:12]
Reactant: C/C=C/C=C/CCCCCCCO
Reactant: CC[Si](Cl)(CC)CC
Solvent: CCN(CC)CC
Product: C/C=C/C=C/CCCCCCCO[Si](CC)(CC)CC
Reaction time: 15 h

Procedure:
A mixture of trans,trans-8,10-dodecadien-1-ol (1.82 g), triethylamine (3.5 ml) and triethyl-chlorosilane (1.85 ml) is held at 25° C. for 15 hours. After dilution of the mixture with hexane (100 ml), it is thoroughly washed with ice-water (3×50 ml), dried (CaSO4), concentrated by evaporation and distilled. The title compound is obtained in the boiling range of 107° to 112° C. (nD20 =1.4697).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](O)=[O:19])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:22]1([NH:21][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:17]3)=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1
Yield: 70 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (30 mg, 0.11 mmol) synthesized in Preparation Example 4, aniline (21 μl, 0.23 mmol), triethylamine (0.20 ml, 1.4 mmol), propanephosphonic acid anhydride (0.3 ml), dimethylaminopyridine (a catalytic amount) and methylene chloride (0.25 ml), a similar procedure to a) in Example 29 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 7:3) to obtain N-phenyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (27 mg, 0.077 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:12][OH:13])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1ncc(C=O)c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ncc(C=NO)c(N)n1
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To 8.6 g of 2-methyl-4-amino-5-formylpyrimidine, while stirring at room temperature in a mixture of 272 ml of methanol and 68 ml of water, was added dropwise 10 ml of an aqueous solution containing 5.1 g of hydroxylamine hydrochloride. The reaction was allowed to proceed for further 4 hours at room temperature. To the reaction solution was added dropwise 30 ml of an aqueous solution containing 3.90 g of sodium carbonate to cause precipitation of crystals. The crystals were collected by filtration and dried under reduced pressure to give 7.45 g (yield 78.2%) of 2-methyl-4-amino-5-pyrimidine aldoxime. The mother liquor was subjected to quantitative determination (by absolute calibration curve method) of 2-methyl-4-amino-5-pyrimidine aldoxime by means of high performance liquid chromatography to confirm that 1.95 g (yield 20.5%) of the object compound was produced. The total yield of the crystals thus obtained and the object compound in the mother liquor was 98.7%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[C:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)=[CH:4][CH:3]=3)[N:35]=2)=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1
Yield: 64 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(4-benzoylphenyl)-4-chloromethyloxazole to give 2-(4-benzoylphenyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 64%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 91-92° C.