Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:65])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51]C(=O)CCCCCCC(O)=O)[CH:47]([O:63][CH3:64])[CH2:46]2)[CH:8]([CH3:66])[CH:7]([OH:67])[CH2:6][C:5]1=[O:68])[CH:2]=[CH2:3].C(Cl)CCl.Cl.ON1C2C=CC=CC=2N=N1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CN(C)C=O>[CH3:32][C@H:27]1[CH2:28][C:29]([CH3:31])=[CH:30][C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:68])[CH2:6][C@H:7]([OH:67])[C@@H:8]([CH3:66])[C@@H:9](/[C:43](/[CH3:65])=[CH:44]/[C@H:45]2[CH2:46][C@@H:47]([O:63][CH3:64])[C@H:48]([OH:51])[CH2:49][CH2:50]2)[O:10][C:11](=[O:42])[C@H:12]2[N:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:18](=[O:41])[C:19](=[O:40])[C@:20]2([OH:39])[O:35][C@@H:24]([C@@H:23]([O:36][CH3:37])[CH2:22][C@H:21]2[CH3:38])[C@@H:25]([O:33][CH3:34])[CH2:26]1
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCCCCCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the 17-allyl-1,14-dihydroxy-12-{2-[4-(7-carboxy-heptanoyl-oxy)-3-methoxy-cyclohexyl]-1-methyl-vinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone prepared in Production Example 2 (38.4 mg, 0.04 mmol), TOYO-Pearl resin (TSKgel AF-amino, 100 μl, free amino group (available amino group) content 0.01 mmol), EDC/HCl (9.2 mg, 0.048 mmol), 1-hydroxybenzotriazol (HOBt; 6.5 mg, 0.048 mmol) and dimethylformamide (DMF; 1 ml) was stirred at room temperature for 6 hours. The reaction end point was confirmed as the time when no residual amino group became visually observable by the ninhydrin reaction. The reaction rate at this time was calculated to be about 82%. After confirmation of completion of the reaction, the resin was washed with DMF five times. Acetic anhydride (100 μl) and DMF (400 μl) were added thereto, and this was followed by stirring at room temperature for 1 hour. Subsequently, the resin was thoroughly washed with DMF, and the TOYO-Pearl resin with FK506 obtained was used in the binding experiments described below. In the groups that interlie between the TOYO-Pearl resin and FK506, the number of HBA is 4 and the number of HBD is 3 (however, those coming from the groups introduced to FK506 in advance are not counted). The number of HBA and the number of HBD come from the commercially available linker of TOYO-Pearl resin.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]1[C:18](=[O:36])[N:19]([C:23]2[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)=[O:27])[CH:20]=[CH:21][N:22]=1.[CH3:37][NH2:38]>O1CCOCC1>[CH:29]1([NH:28][C:26](=[O:27])[C:25]2[CH:32]=[CH:33][C:34]([CH3:35])=[C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:17]([N:13]4[CH2:14][CH2:15][CH2:16][CH:12]4[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH2:3][CH2:2][NH:38][CH3:37])[C:18]3=[O:36])[CH:24]=2)[CH2:31][CH2:30]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCCC2c2ccccc2OCCCCl)c1=O
Reactant: CN
Solvent: C1COCCO1
Product: CNCCCOc1ccccc1C1CCCN1c1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O

Procedure:
3-[3-{2-[2-(3-Chloropropoxy)phenyl]pyrrolidin-1-yl}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide (Example 324b, 0.23 g) and methylamine (1 mL) were heated in a CEM microwave in dioxane at 110° C. for 15 min. The resulting solution was concentrated in vacuo and purification by preparative HPLC (X-Bridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile) gave the title compound as a solid (0.028 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C1CNCCN1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCNC(=O)C2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. LC-MS: 595.2 [(M+H)+]
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[Cl:34])[N:30](COCC[Si](C)(C)C)[N:29]=[C:28]3[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[Cl:34])[NH:30][N:29]=[C:28]3[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Temperature: 67 °C

Procedure:
8.8 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 650 mg of N-[5-phenyl-6-chloro-1-[[2-(trimethylsilyl]ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 25 cm3 of tetrahydrofuran. The medium is maintained at 67° C. for 20 hours and is then allowed to return to room temperature and 75 cm3 of ethyl acetate are added; the organic phase is washed with 75 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×75 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 15 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 10 cm3 of diisopropyl ether and with 5 cm3 of ethyl acetate. After drying under reduced pressure (90 Pa; 50° C.), 240 mg of N-(5-phenyl-6-chloro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 235° C.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:24])[CH:4]=1)#[CH:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:24])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 91 %

Procedure:
4-(4-Ethynyl-2-fluoroanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-(4-ethyl-2-fluoroanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (91%), m.p. (EtOAc) 231-233° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.28 (br s, 1H), 10.02 (s, 1H), 8.41 (t, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.32 (t, J=8.3 Hz, 1H), 7.19 (dd, J=11.9, 1.8 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 5.33 (s, 1H), 4.44 (t, J=5.1 Hz, 1H), 3.46 (q, J=5.2 Hz, 2H), 3.30-3.22 (m, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.66 (pentet, J=6.7 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). Anal. Calcd for C17H20FN3O3: C, 61.1; H, 6.1; N, 12.6. Found: C, 61.3; H, 5.9; N, 12.7.
Reaction SMILES: [OH:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CO.[Pd]>[OH:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1/C=C/CC(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCC(O)Cc1ccccc1
Yield: 86.9 %

Procedure:
A solution of 30c (2.59 g, 8.75 mmol) in MeOH (100 mL) was hydrogenated using 10% Pd/C (0.93 g, 0.88 mmol) as catalyst at atmospheric pressure overnight. The catalyst was removed by filtration, and the solution was evaporated at reduced pressure to afford the desired product (2.27 g, 97% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH:8]=[CH2:9])(=[O:3])[CH3:2].[C:10](O)(=[O:14])[C:11](C)=C.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:14][CH:10]=[CH2:11])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)O
Reactant: C=COCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=COCCOCCOC(C)=O
Yield: 93 %

Procedure:
The thus obtained acetoxyethylvinylether by 19.5 grams (0.15 mols) and methacrylic acid by 15.5 grams (0.18 mols) were dissolved into methylene chloride. Then, 0.38 grams (0.0015 mols) of p-toluenesulfonic acid pyridine salt was added into the mixture, and stirred for complete dissolution. The resultant mixture is stood at room temperature for 6 hours. Then, the mixture was washed three times with 2.5% aqueous sodium hydroxide, and six times with water. Then, the resultant mixture was dehydrated with magnesium sulfate. After filtering magnesium sulfate out, solvent was removed by means of an evaporator. Then, the resultant residue was distilled under reduced pressure, thereby there was obtained 29.6 grams of acetoxyethoxyethylvinylether (b.p. 100-105° C./0.07 mmHg). The yield was 93%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:19])=[O:8])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.C1COCC1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>O.CO>[NH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:19])[C:10]=1[NH:9][C:7]([C:5]1[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=[C:2]([Br:1])[CH:6]=1)=[O:8]
Reactant: Cc1cccc([N+](=O)[O-])c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cccc(N)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-nitrophenyl)-1H-pyrazole-5-carboxamide prepared in Step 1 (1.27 g, 2.91 mmol), THF (0.2 M, 14.6 mL) and Na2S2O4 (5.37 g, 26.2 mmol, 9.0 eq) were added to a 100 mL round flask and stirred. In a separate flask, NaHCO3 (2.20 g, 26.2 mmol, 9.0 eq) was dissolved in H2O (0.1 M, 29.1 mL) and slowly added to the reaction solution. MeOH (0.6 M, 4.9 mL) was added to the reaction solution, subjected to a reaction at room temperature for 5 minutes, and the solvent was removed therefrom under reduced pressure upon completion of the reaction. The residue was extracted with ethyl acetate (20 mL x 2) and brine (20 mL x 2), and the organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Upon completion of removing the solvent, the residue was dissolved in a small quantity of ethyl acetate, wetted with ethyl acetate/hexane (1:1) and then filtered. The solvent was removed under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([N:17]([CH3:42])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:27])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(NC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In N,N-dimethylformamide (10 ml), 1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (147 mg) was dissolved. After the addition of 60% oily sodium hydride (22 mg), the resulting mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.023 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 90 minutes. To the residue obtained by concentrating the reaction mixture under reduced pressure, ethyl acetate was added. The resulting mixture was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (43 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:17]1[CH:22]=[C:21]([CH2:23]Br)[CH:20]=[CH:19][N:18]=1)#[N:16]>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([C:15]#[N:16])[CH:22]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1cc(CBr)ccn1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccnc(C#N)c2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 122, Part F using 2-cyano-4-(bromomethyl)pyridine in place of 4-bromomethylthiophene-2-carbonitrile. The crude product is purified by column chromatography eluting with gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=[CH:5][C:6]=1[Cl:9]
Reactant: Cc1c(Cl)ccc(-c2ccccc2)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccccc2)c(Cl)c1CBr
Yield: 99.1 %

Procedure:
A stirred solution of 10.6 g (0.045 mole) of 2,4-dichloro-3-methyl[1,1'-biphenyl] and 8.0 g (0.045 mole) of N-bromosuccinimide in 100 ml of carbon tetrachloride was irradiated with a 250 watt infra-red lamp for 4 hours. The reaction mixture was allowed to reflux from the heat of the lamp during the 4 hour period. The reaction mixture was filtered and the filter cake was washed with one portion of 100 ml of carbon tetrachloride. The wash and filtrate were combined and washed with one portion of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give 14.1 g of 3-bromomethyl-2,4-dichloro[1,1'-biphenyl]. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1.[BH4-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2c(F)cccc2Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: OCc1csc(-c2c(F)cccc2Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cooled (0° C.) solution of ethyl 2-(2-chloro-6-fluorophenyl)thiazole-4-carboxylate (7.0 g, 25 mmol) in MeOH (100 mL) was added lithium borohydride (1.62 g, 73.8 mmol) in four portions. After addition, the resulting mixture was stirred at 0° C. for 1 hour. The mixture was quenched with water (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography, eluting with EtOAc/petroleum ether (1:5) to give the desired product as a white solid (5.8 g, 98% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.74 (s, 1H), 7.35-7.41 (m, 1H) NOT ENOUGH AR PROTONS, 5.47 (s, 1H), 4.67 (m, 2H). LCMS (ESI) m/z: 244.1 [M+H+].
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a stirred solution of (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (209 g, 0.80 mol) in absolute CH2Cl2 (3 L) at 0° C. under N2 was added dropwise TiCl4 (92.2 mL, 0.84 mol) over 30 min. After 15 min, DIEA (0.864 mol) was added dropwise over 15 min, and stirring was continued for 1 h at 0° C. ((Chloromethoxy)methyl)benzene (222 mL, 1.60 mol) was added dropwise over 90 min at 0° C. After stirring for 20 h at 0° C., the reaction was quenched by addition of 10% aq NH4Cl (800 mL) and H2O (1 L). The aqueous phase was extracted with CH2Cl2 (2×1 L), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel to afford (R)-4-benzyl-3-((S)-2-(benzyloxymethyl)-3-methylbutanoyl)oxazolidin-2-one (152 g, 50%). 1H NMR (400 MHz, CDCl3): 0.99 (m, 6H), 2.05 (m, 1H), 2.67 (m, 1H), 3.23 (m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 4.14 (m, 3H), 4.52 (m, 2H), 4.72 (m, 1H), 7.26 (m, 10H).
Reaction SMILES: O[CH2:2][C@@H:3]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:9])[CH2:4][CH2:5][CH3:6].CC(C)([O-])C.[K+].O>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH2:2][C@H:3]([CH2:4][CH2:5][CH3:6])[NH:7][C:8]2=[O:9])=[CH:12][CH:13]=1
Reactant: CCC[C@@H](CO)NC(=O)Nc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1
Reaction time: 1 h
Yield: 6.7 %

Procedure:
A solution of 1-[(2S)-1-hydroxypentan-2-yl]-3-(4-methoxyphenyl)urea (550 mg) and potasium tert-butoxide (593 mg) in THF (25 mL) was cooled in ice under nitrogen atomosphere, and a solution of p-toluenesulfonylchrolide (672 mg) in THF (10 mL) was added dropwise thereto. After the mixture was stirred for 1 hr while cooling in ice, water was added thereto, and the resulting mixture was extracted with chloroform. The organic layer was separated out by phase-separation cartridge, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=88:12-0:100), and further recrystallized from chloroform/hexane. The solid was collected by filtration to afford (4S)-1-(4-methoxyphenyl)-4-propylimidazolidin-2-one (34 mg). In addition, the filtrate was concentrated under reduced pressure to afford (4S)-1-(4-methoxyphenyl)-4-propylimidazolidin-2-one (254 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[NH:24][CH:23]=[CH:22]3)[CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[NH:24][CH:23]=[CH:22]3)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=c1[nH]ccc2cc(O[C@H]3CCCNC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cc(O[C@H]3CCCN(CCOCc4ccccc4)C3)ccc12
Reaction time: 17 h

Procedure:
2-Benzyloxyethyl bromide (1 mol) was added to a suspension of (S)-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol) and potassium carbonate (70mg, 4.2 mol) in N, N-dimethylformamide (500 μl) and shaken for 17 hours. The reaction was quenched with hydrochloric acid (2M) and methanol and passed down an SCX cartridge. The products were purified by preparative HPLC under basic conditions. The clean products were isolated by evaporation under reduced pressure to afford (S)-6-[1-(2-benzyloxyethyl)piperidin-3-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=379.4[M+H]+.
Reaction SMILES: [OH-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[N+:30]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([O-:32])=[O:31].Cl>CS(C)=O>[N+:30]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[CH:10][CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])([O-:32])=[O:31]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A mixture of 1.6 g of sodium hydroxide (60%, oil) in 60 ml of dimethylsulfoxide was stirred at 55°~60° C. for 1 hour. After lowering to room temperature, a solution of 9 g of (4-carboxybutyl)triphenyl phosphonium bromide in 20 ml of dimethylsulfoxide was added to the mixture. After stirring at room temperature for 30 minutes, a solution of 3 g of o-nitrobenzaldehyde in 10 ml of dimethylsulfoxide was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into cold diluted hydrochloric acid followed by extraction with ether. After washing with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain oily 6-(o-nitrophenyl)-5-hexenic acid. This substance was added to a mixture of 20 ml of ethanol and 4 ml of conc. surfuric acid. The resulting mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue followed by extracting with toluene. The extract was washed with water, a diluted aqueous sodium hydrogen carbonate and water, in order. After drying over anhydrous magnesium sulfate, the system was concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with toluene to obtain 0.73 g of ethyl 6-(o-nitrophenyl)-5-hexenate.