Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][CH:13]=O.C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:11][C:5]1[CH:4]=[C:3]([CH2:12][CH2:13][N:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)[C:2]([Cl:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CCc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCc2cc(Cl)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A methylene chloride solution of the title compound of Example 10 was stirred at room temperature under nitrogen. Acetic acid (8.8 ml, 153 mmol) was added in one portion followed by t-butylpiperazinecarboxylate (8.4 g, 50 mmol). Sodium triacetoxy-borohydride (16.2 g, 77 mmol) was added in portions as a solid and the reaction mixture stirred at room temperature for three hours. The reaction mixture was washed two times with excess saturated sodium carbonate solution and one time each with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title product as an oil 15.6 g, (98% crude yield). This was suitable for use in the next reaction without further purification. NMR (CDCl3) δ 7.92 (s, 1), 7.48 (s, 1), 3.43 (m, 4), 2.97 (t, 2), 2.62 (t, 2), 2.49 (m, 4), 1.43 (s, 9).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:20][CH2:21][O:22][CH3:23])=[N:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:8]=1[CH3:9].[CH2:24]([O:26][C:27](=[O:40])[C:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH3:39])([CH3:30])[CH3:29])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:24]([O:26][C:27](=[O:40])[C:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:2][C:3]2[C:4]([CH2:20][CH2:21][O:22][CH3:23])=[N:5][C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:7][C:8]=2[CH3:9])=[CH:34][C:33]=1[CH3:39])([CH3:29])[CH3:30])[CH3:25]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C
Yield: 51.8 %

Procedure:
A solution of 350 mg (1 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 118G]), 235 mg (1 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 417 mg (1 mmol) cesium carbonate in 5 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 283 mg of pure 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:17])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:3]=1[CH2:4][Cl:17]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)Nc1cccc(C)c1CO
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C)c1CCl

Procedure:
To a suspension of 2-methyl-6-methoxycarbonylaminobenzyl alcohol (29.19 g) in methylene chloride (290 ml) was added dropwise thionyl chloride (11.46 ml) at room temperature and the resultant mixture was stirred for 2 hours. After the solvent was evaporated in vacuo, n-hexane was added to the residue to give precipitates. The precipitates were collected by filtration and dried to give 2-methyl-6-methoxycarbonylaminobenzyl chloride (28.26 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15].C(N(CC)CC)C>C(O)(C)C>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][NH:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1NCC(O)CO
Yield: 61 %

Procedure:
A solution of 2-chloro-3-nitropyridine (3.22 g, 20.3 mmol), 3-amino-1,2-propanediol (1.85 g, 20.3 mmol) and triethylamine (2.05 g, 20.3 mmol) in isopropanol (80 mL) was stirred at 20°-25° C. for 18 hours and then at reflux for 6 hours. After concentrating under reduced pressure, the residue was flash chromatographed over silica gel. Elution with 5% MeOH-95% CHCl3 and recrystallization from EtOAc-hexane afforded analytically pure product (2.64 g, 61%), m.p. 95.5°-98.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[K+].[CH2:20](Cl)[CH:21]=[CH2:22].[I-].[K+]>O1CCCC1>[CH2:22]([O:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH:21]=[CH2:20]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: C=CCCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOc1cc(OC)ccc1C(=O)c1ccccc1

Procedure:
2-Hydroxy-4-methoxybenzophenone (114 parts) was dissolved in tetrahydrofuran (100 parts). Potassium hydroxide (30.9 parts) was added. By heating and stirring, complete dissolution was achieved. Allyl chloride (46.4 parts) and potassium iodide (4.2 parts) were added to this solution, which was then heated and refluxed for 8 hours. After cooling, it was washed with water and the solvent was removed by distillation. A crude product of the desired 2-allyloxy-4-methoxybenzophenone was obtained. It was recrystallized in n-hexane to obtain 125 parts of 2-allyloxy-4-methoxybenzophenone (melting point 40° C.) at 93% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(CS(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(methylsulfinylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[C:7](B(O)O)[CH:8]=1.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2Br)[CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:7]2[CH:8]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=[CH:5][C:6]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:30]=1)=[O:28])[CH3:25]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Reactant: CCOC(=O)c1ccnc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1ccnc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using [5-trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)-boronic acid and 2-(bromocyclopent-1-enyl)pyridine-4-carboxylic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester
Reaction SMILES: [N:1]1([C:7]2[CH:38]=[CH:37][C:10]([CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22]CC5C=CC=CC=5)=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[N:1]1([C:7]2[CH:38]=[CH:37][C:10]([CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]3[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(N3CCCCC3)cc2)cc1
Agent: [Pd]
Product: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(N2CCCCC2)cc1

Procedure:
1-{4-(N-Piperidyl)benzyl}-2-(4-fluorophenyl}-6-phenylmethoxy-1,2,3,4-tetrahydroisoquinoline (0.25 g, 0.49 mmol) was treated with H2 in 10% Pd/C as described in Example 14.D to yield 1-{4-(N-piperidyl)benzyl}-2-(4-fluorophenyl}-1,2,3,4-tetrahydroisoquinoline-6-ol. Treatment of the free base with conc. HCl in ether produces a fine white solid. The precipitate is filtered and dried under high vacuum to yield the title compound. (0.096 g, 47% yield): m.p. 177-179° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:15])=[N:4][C:5]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:15][C:16](=[O:18])[CH3:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(OCc2cccs2)ncc1F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)Nc1nc(OCc2cccs2)ncc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
In a 2 dram screw cap vial, a solution of 5-fluoro-2-(thiophen-2-ylmethoxy)-pyrimidin-4-ylamine (0.10 g, 0.4 mmol) in CH2Cl2 was treated with acetyl chloride (0.032 g, 0.4 mmol) and PS-NMM (0.42 g, 0.8 mmol), a resin-bound equivalent of N-methyl morpholine (NMM). The mixture was shaken at RT for 12 h. The reaction mixture was filtered and the solvent evaporated to yield 0.084 g (75%) of the title compound as white solid: mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.6 Hz, 1H), 7.86 (bs, 1H), 7.31 (m, 1H), 7.23 (m, 1H), 7.00 (m, 1H), 5.54 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1>[Cl-].[Zn+2].[Cl-]>[C:2]1([CH:1]=[CH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccnnc1
Agent: [Cl-]
Agent: [Zn+2]
Product: C(=Cc1ccnnc1)c1ccccc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
Zinc chloride (820 mg, 6 mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60 mmol) and 4-methylpyridazine (2.83 g, 30 mmol) and the resulting mixture heated for 20 hours at 150° C. The cool reaction mixture was partitioned between dichloromethane (40 ml) and 2M aqueous sodium hydroxide solution (20 ml), then the organic phase separated, combined with a dichloromethane extract (80 ml) of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure. The residual pale brown oil was purified by column chromatography on silica gel, using dichloromethane:methanol (99:1) as eluant, to give the title compound (3.65 g) as a pale brown solid. Found: C, 78.95; H, . 5.52; N, 15.39. C12H10N2 requires C, 79.10; H, 5.53; N, 15.37%. δ (CDCl3): 6.96 (1H, d), 7.45 (5H, m), 7.55 (2H, m), 9.12 (1H, d), 9.30 (1H, s). LRMS: m/z 183 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:19]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-cyanoindole (1.0 g, 7.0 mmol) in dichloromethane (8 mL) was added 4-(dimethylamino)pyridine (0.171 g, 1.4 mmol), triethylamine (1.96 mL, 1.42 g, 14 mmol) and benzoyl chloride (0.89 mL, 1.08 g, 7.7 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture was diluted with dichloromethane (80 mL) and washed consecutively with a saturated solution of sodium hydrogencarbonate (40 mL) and brine (40 mL). The organic phase was dried with magnesium sulfate (1 hour). Filtration and concentration furnished the crude material which was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes=2:3. 1-Benzoyl-1H-indole-5-carbonitrile was obtained as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[N+]=[N-])[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[CH2:29]([OH:31])[CH3:30]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([O:31][CH2:29][CH3:30])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]
Reactant: CCO
Agent: [Rh]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Rhodium (II) acetate dimer (33 mg) was added to a mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-diazopropanoate (2.80 g), ethanol (2.16 mL) and benzene (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes, heated at reflux for a further 15 minutes, then cooled and evaporated in vacuo. The residue was chromatographed on silica gel using 1.5% methanol in dichloromethane as eluent to afford the title compound as a gum.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:12]#[N:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]#[N:13])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: N#CC(=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution sodium ethoxide is added benzyl cyanide and N-benzyl-4-piperidone (XI-1) and the reaction is run at 85° C. for 3 h. Workup with concentrated hydrochloric gives the intermediate (1-benzyl-piperidin-4-yl-idene)-phenyl-acetonitrile which is treated with potassium cyanide. Reduction of one carbonyl group is performed with an excess of diisobutylaluminium hydride and elimination is performed with acetic acid. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF3)2C6H3COCl is added to give a compound of formula I-13.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[N:11]=[C:12]([SH:24])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]1[O:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]3[N:13]4[C:12]([S:24][CH2:26][CH2:27]4)=[N:11][C:10]=3[C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[CH:16][C:17]=2[O:23]1
Reactant: BrCCBr
Reactant: Sc1nc(-c2ccc3c(c2)OCO3)c(-c2ccc3c(c2)OCO3)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc2c(cc1-c1nc3n(c1-c1ccc4c(c1)OCO4)CCS3)OCO2
Temperature: 0 °C

Procedure:
A slurry of 3.5 g. (0.01 mole) of 4,5-bis(3,4-methylenedioxyphenyl)-2-mercaptoimidazole, 2.0 g. (0.01 mole) of 1,2-dibromoethane and 2 g. (0.014 mole) of potassium carbonate in dimethylformamide (45 ml.) was refluxed for 2.5 hours and then poured into 500 ml. of ice water. The precipitate was collected, washed with water and dried. Chromatography (alumina/chloroform) gave 5,6-bis(3,4-methylenedioxyphenyl)-2,3-dihyroimidazo[2,1-b]thiazole. This was dissolved in methanol and treated with aqueous hydrobromic acid. The solvent was removed and the residue recrystallized from methanol to give 5,6-bis(3,4-methylenedioxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole hydrobromide, m.p. 278°-280° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18](Cl)=[O:19]>C1(C)C(C)=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)c(Cl)c2)n1C
Yield: 79.6 %

Procedure:
A solution of 3.6 g of ethyl 1,4-dimethylpyrrole-2-acetate and 8.3 g of 3,4-dichlorobenzoyl chloride in 20 ml of xylene is refluxed for 40 min and then chilled. The separated solid is collected by filtration and dried to give 5.6 g (80%) of ethyl 5-(3,4-dichlorobenzoyl)-1,4-dimethylpyrrole-2-acetate as white crystals, m.p. 92°-93.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:20]([CH:25]([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)F)c2)COC(C)(C)OC1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 30-4 (600 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (412 mg) and 1-bromooctane (0.311 ml) were added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-3:1) to give the object product (230 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39]>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:30])([CH3:29])[CH3:28])[P:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=Nc2ccccc2C(C)(C)C)Nc2ccccc2C(C)(C)C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(C(=Nc2ccccc2C(C)(C)C)N(c2ccccc2C(C)(C)C)P(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
N′-(2-tert-butylphenyl)-N-(2-tert-butylphenyl)-4-methylbenzamidine (NS Amidine II) (1.20 g, 3.0 mmol) was dissolved in 50 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a light yellow solution. The solution was warmed to room temperature and stirred for 2 hours. Chlorodiisopropylphosphine (0.48 mL, 3.0 mmol) was added slowly at room temperature. A white suspension formed, which was stirred overnight at room temperature. The slurry was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo to produce 1.35 g (87%) of yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:21])[CH3:20]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]=[CH:20][C:19](=[O:21])[CH3:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)C=CCCc1ccc(OCc2ccccc2)cc1
Yield: 105.5 %

Procedure:
A solution of 21.2 g of 3-(p-benzyloxyphenyl)propionaldehyde and 30.9 g of acetylmethylenetriphenylphosphorane in 120 ml of tetrahydrofuran was heated under reflux for 4.5 hours, the solvent was then evaporated and the residual crystals were recrystallized from a mixture of n-hexane and ether (5:1) to give 26.1 g of the desired compound melting at 70°-72° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:4]([OH:21])[CH2:3][OH:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
A solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyric acid methyl ester 99 g dissolved in ethanol 130 ml was kept at 15-25° C. and mixed with sodium borohydride 15.7 g and stirred at 15-25° C. for 2.5 hrs. The reaction solution was diluted with water, adjusted with 6N-HCl to pH 2.5-3.5 and thereafter the solvent was distilled away to half the volume of the resultant solution, and then ethyl acetate was added to the solution. The solution thus obtained was washed with water and aqueous 10% sodium chloride solution successively to separate an organic phase. The solvent in the organic phase was distilled away and then ethyl acetate was added to the resultant concentrated solution to cool it and n-heptane was added to the solution halfway. Further n-heptane was added to the cloudy solution obtained. Thereafter, the solution was stirred at 10° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol(65.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]([O:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:14]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:16]([O:15][CH2:13][CH3:14])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CCONCc1ccc(F)cc1
Product: CCON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-ethyl-N-4-fluorobenzyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (92% yield): mp 95-96° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.07 Hz, CH3), 1.77 (6H, s, CH3), 3.90 (2H, q, J=7.07 Hz, OCH2), 4.81 (2H, s, NCH2), 6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.50; H, 5.60; N, 4.17.