Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:30][CH3:31])[C:10](=[O:29])[CH2:11][N:12]2[C:20]3[C:15](=[N:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][CH:19]=3)[N:14]([CH3:27])[C:13]2=[O:28])=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:30][CH3:31])[C:10](=[O:29])[CH2:11][N:12]2[C:20]3[C:15](=[N:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][CH:19]=3)[N:14]([CH3:27])[C:13]2=[O:28])=[CH:5][CH:4]=1
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47.4 %

Procedure:
To a mixture of 8,9-dihydro-N-(4-methoxyphenyl)-9-methyl-N-ethyl-8-oxo-2-phenyl-7H-purin-7-acetamide (0.83 g) obtained in Example 173 and dichloromethane (10 ml) is added a 1M solution of boron tribromide in dichloromethane (4 ml) at 0° C., and the mixture is stirred at room temperature for five days. To the reaction mixture is added water, and the precipitates are collected by filtration, washed with water, and recrystallized from ethanol and diisopropyl ether to give the desired compound (0.38 g).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[CH:27][CH:26]=1>C1COCC1.C(=O)=O.CO>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:33](=[O:34])[CH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1ccc(-c2ccccc2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCc1ccc(-c2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -60.5 °C
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
To a 1.6 M solution of n-BuLi in hexane (12.1 mL, 19.3 mmol) is added dropwise a solution of (S)-(−)-4-benzyl-2-oxazolidinone (3.26 g, 18.4 mmol) in dry THF (80 mL) at −71.6° C. under nitrogen over 10 minutes. The solution is warmed up to −60.5° C. while the addition, and allowed to stir for 1 hour in dry ice/MeOH bath. 3-(Biphenyl-4-yl)propanoyl chloride (intermediate 13: 5.46 g, 22.31 mmol) in dry THF (20 mL) is added dropwise at −72° C. over 5 minutes. The solution is warmed up to −56.5° C. while the addition. After stirring 10 minutes at the same temperature, the reaction mixture is allowed to warm to room temperature and stirring is continued for 3 hours. The reaction mixture is filtered, and the collected precipitate is washed with 20 mL (10 mL×2) of MeOH and then with 150 mL of H2O to give the desired product (4.26 g). The products in the mother liquor is extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is suspended in 80 mL of MeOH, and the suspension is filtered and washed with 20 mL of MeOH (1.79 g). The two fractions are mixed to give (S)-4-benzyl-3-(3-(biphenyl-4-yl)propanoyl)oxazolidin-2-one (6.05 g, 85% in 2 steps). Retention time=1.77 minutes (condition A); MS (m+1)=387.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.77 (dd, J=13.39, 9.35 Hz, 1H) 2.99-3.15 (m, 2H) 3.20-3.43 (m, 3H) 4.09-4.24 (m, 2H), 4.68 (dddd, J=9.76, 6.73, 3.47, 3.28 Hz, 1H) 7.18 (d, J=7.07 Hz, 2H) 7.23-7.37 (m, 6H) 7.42 (t, J=7.58 Hz, 2H) 7.53 (d, J=8.1 Hz, 2H), 7.57 (d, J=7.8 Hz, 2H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].F[C:20]1[C:21]([O:33][CH3:34])=[C:22]2[C:26](=[CH:27]C=1)N(C)C=C2CCO.[N:35]([CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:57])[C:47]=2[O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:42][CH:41]=1)=[N+:36]=[N-:37]>>[N:35]([CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:57])[C:47]=2[O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:42]([CH2:20][CH:21]2[CH2:22][CH2:26][CH2:27][CH2:34][O:33]2)[CH:41]=1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=NCCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Reactant: COc1c(F)ccc2c1c(CCO)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: [N-]=[N+]=NCCc1cn(CC2CCCCO2)c2ccc(F)c(OCc3ccccc3)c12
Yield: 82 %

Procedure:
Following the procedure (step 5, scheme 17, TBAF deprotection step unnecessary) used to prepare compound 17-6, compound 19-1 gave compound 19-2 in 82% yield as a colorless oil. 1H NMR (CDCl3, 300 MHz) (ppm): 7.25-7.47 (m, 5H), 6.91-6.97 (m, 3H), 3.91-4.04 (m, 3H), 3.58 (m, 1H), 3.36-3.43 (m, 3H), 2.97 (t, J=6.9 Hz, 2H), 1.23-1.48 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23]S(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:49])[C:38]([O:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([CH3:40])[CH3:39])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:49])[C:38]([O:41][C:42]1[CH:47]=[CH:46][C:45]([O:23][CH2:22][CH2:21][C:19]2[N:20]=[C:16]([C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=3)[O:17][CH:18]=2)=[CH:44][CH:43]=1)([CH3:40])[CH3:39])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Yield: 70 %

Procedure:
Toluene-4-sulfonic acid 2-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethyl ester (Eli Lilly and Co, Eur. Pat. Appl. 98-308063) (490 mg, 1.04 mmol) was coupled to 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (203 mg, 0.90 mmol) following the procedure described in Example 1 to provide the product (330 mg, 70%) as a clear, colorless oil:
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)(=O)C.[CH3:12][N:13]([CH3:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:16][CH:15]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:21][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([N:13]([CH3:34])[CH3:12])=[CH:19][CH:18]=2)[C:22]2[C:23](=[CH:27][C:28]([N:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)[C:24](=[O:26])[O:25]1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21
Temperature: 47 °C

Procedure:
To a stirred mixture of 30.0 ml of acetic anhydride and 15.0 ml of glacial acetic acid there was added gradually 5.0 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid. The reaction mixture was heated slowly to approximately 47° C. and maintained at a temperature in the range of 45° to 50° C. for approximately thirty minutes. The resultant mixture was cooled to ambient temperature, stirred approximately forty-five minutes and then cooled to approximately 0° C. A solution of 15.0 ml of methyl alcohol and 19.4 ml of pryidine was added dropwise to the reaction mixture while maintaining a temperature of approximately 0° C. The resulting mixture was allowed to stir at ambient temperature for approximately two hours. After adding toluene to the reaction mixture, five percent aqueous ammonium hydroxide was added slowly until the resulting mixture was slightly alkaline. The toluene layer was separated from the alkaline water layer and toluene was removed under reduced pressure to obtain 4.67 g of 3-methoxy-3(4-dimethylaminophenyl)-6 -dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green-colored solid which melted at 140° to 147° C. A significant infrared maximum appeared at 1760 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. A toluene solution of the product spotted on an acid-clay coated paper developed a turquoise-colored image.
Reaction SMILES: O=[C:2]1C2C3C(C(OC)=O)=CC=CC=3NC=2CN[CH2:3]1.C(=O)CC.[CH3:23][N:24]1[CH2:36][C:35]2[NH:34][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:37](=[O:40])[NH:38][N:39]=[C:26]([C:27]=2[C:28]=34)[CH2:25]1>>[CH2:23]([N:24]1[CH2:36][C:35]2[NH:34][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:37](=[O:40])[NH:38][N:39]=[C:26]([C:27]=2[C:28]=34)[CH2:25]1)[CH2:2][CH3:3]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Solvent: CCC=O
Product: CCCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 56 was prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and propionaldehyde according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.92 (s, 1H), 7.47 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.8 Hz), 7.13 (t, 1H, J=7.8 Hz), 3.81 (s, 2H), 3.28 (s, 2H), 2.50-2.55 (m, 2H), 1.51-1.54 (m, 2H), and 0.89 (t, 3H, J=7.8 Hz). MS (ESI) m/e [M+1]+ 269.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]1([CH3:20])[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1>>[CH3:20][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Cc1cccc(C)c1
Product: Cc1cccc(CON2C(C)(C)CC(O)CC2(C)C)c1
Temperature: 135.5 °C
Yield: 25.2 %

Procedure:
A mixture of 8.60 g (0.05 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere is heated at 135-136° C. for 69 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10 w/v % ascorbic acid (3×33 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 3.50 g (51% yield) of a white solid melting at 66-67° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([O:16][CH:13]([CH3:15])[CH3:14])[N:7]=1)#[N:10]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CC(C)O
Product: CC(C)Oc1nc(C#N)c(C#N)nc1Cl
Yield: 45 %

Procedure:
Isopropanol (50 ml) was added to 1.99 g (0.01 mole) of 2,3-dicyano-5,6-dichloropyrazine, and the mixture was refluxed for 10 hours. After the reaction, the isopropanol was distilled off under reduced pressure. The crude product obtained (1.14 g) was chromatographed on a column of silica gel using benzene-n-hexane as an eluent to afford 1.00 g (yield 45%) of 2,3-dicyano-5-chloro-6-isopropoxypyrazine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:25]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:27][CH2:26][C:25]3[C:28]([F:33])=[CH:29][CH:30]=[C:31]([F:32])[C:24]=3[F:23])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NCc1c(F)ccc(F)c1F
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Yield: 94 %

Procedure:
4-[3-(3-Cyanophenyl)-ureido]-benzenesulfonyl chloride (1.0 g, 2.98 mmol) was dissolved in 20 ml THF, 2,3,6-trifluoro-benzylamine (0.48 g, 2.98 mmol) and DIEA (0.52 ml, 2.98 mmol) were added and the solution was refluxed for about 3 h. The solvent was removed in vacuo and the residue cristallized with ethanol/water. The solid was filtered and dried in vacuo. Yield 94% of 4-[3-(3-cyano-phenyl)-ureido]-N-(2,3,6-trifluorobenzyl)-benzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[C:17]2[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:16]=2[C:15]([F:23])=[CH:14][CH:13]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:10]1[N:18]2[CH2:19][CH2:20][C:21]3[CH2:22][CH2:16][C:15]([F:23])=[CH:14][C:13]([C:17]=32)=[CH:12][N:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCCC2
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C1=NC=C2C=C(F)CCC3=C2N1CC3
Yield: 98.7 %

Procedure:
A solution of [(S)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (270 mg, 0.768 mmol) in AcOH (4 mL) was stirred at 80° C. for 1 h, then concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, gradient 30-60% EtOAc in cyclohexane) affording the title compound as a pale pink gum (252.6 mg, 99%). LCMS (Method B): RT 2.63 min [M+H]+ 334
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:13]([CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:18][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: BrCCOC1CCCCO1
Reactant: CCCCC(Cc1ccc(O)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCC(Cc1ccc(OCCOC2CCCCO2)cc1)C(=O)OCC
Yield: 83.7 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-(4-hydroxybenzyl)caproate (2.40 g), which is the product of Reference example 6(c), 2-(2-bromoethoxy)tetrahydropyran (1.63 g) and potassium carbonate (3.23 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (2.47 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Na].[C:8](OCC)(=[O:17])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.C(O)(=O)C>O>[CH2:15]([O:14][C:12]([C:10]1[C:6]2[CH:5]=[N:4][NH:3][C:2]=2[N:1]=[C:8]([OH:17])[CH:9]=1)=[O:13])[CH3:16]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)nc2[nH]ncc12
Temperature: 85 °C
Yield: 28.4 %

Procedure:
To a solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) were added a solution of diethyl oxalacetate sodium salt (567 g, 2.7 mol) in water (1.3 L) and then acetic acid in 4 portions (0.8 L). The reaction mixture was heated at 85° C. for 15 hours then cooled to room temperature and filtered. The precipitate was washed with water and then dried to afford the title compound as an orange solid (159 g, 28%). 1H NMR (250 MHz, DMSO): δ 1.35 (t, 3H), 4.36 (q, 2H), 6.69 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:56]1([NH:62][C:63]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][CH:64]=2)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C=O)C.O>[O:20]=[C:21]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:30][CH2:31]1)[CH2:22][C:23]([NH:69][C:66]1[CH:65]=[CH:64][C:63]([NH:62][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:68][CH:67]=1)=[O:25]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(Nc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
HOBt (70 mg, 0.5 mmol) and DIEA (11 mg, 0.9 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (50 mg, 0.3 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (80 mg, 0.5 mmol) followed by N-phenyl-benzene-1,4-diamine (100 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (10% methanol in chloroform) to afford 15 mg (10%) of 3-oxo-N-(4-phenylamino-phenyl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 511.19 (M+1)+, 96.55%, 1H NMR: (CDCl3): δ 7.7 (m, 1H), 7.6 (m, 2H), 7.4 (m, 4H), 7.1 (m, 1H), 7.0 (m, 3H), 6.8 (m, 1H), 4.0 (m, 2H), 3.8 (m, 2H), 3.4 (m, 3H), 3.2 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:17][C:15](=[O:16])[C@H:14]([CH3:18])[C@H:13]([O:19][C@@H:20]2[O:25][C@@H:24]([CH3:26])[C@H:23]([OH:27])[C@@:22]([O:29][CH3:30])([CH3:28])[CH2:21]2)[C@H:12]([CH3:31])[C@@H:11]([O:32][C@@H:33]2[O:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([N:40]([CH3:42])[CH3:41])[C@H:34]2[OH:43])[C@@:10]([OH:45])([CH3:44])[CH2:9][C@@H:8]([CH3:46])[C@H:7]([NH2:47])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C[O:53][CH:54](OC)[CH2:55][P:56]([O:61][CH2:62][CH3:63])([O:58][CH2:59][CH3:60])=[O:57].O1CCOCC1>O>[CH2:62]([O:61][P:56]([CH2:55][CH:54]=[O:53])([O:58][CH2:59][CH3:60])=[O:57])[CH3:63].[CH3:1][CH2:2][C@H:3]1[O:17][C:15](=[O:16])[C@H:14]([CH3:18])[C@H:13]([O:19][C@@H:20]2[O:25][C@@H:24]([CH3:26])[C@H:23]([OH:27])[C@@:22]([O:29][CH3:30])([CH3:28])[CH2:21]2)[C@H:12]([CH3:31])[C@@H:11]([O:32][C@@H:33]2[O:38][C@H:37]([CH3:39])[CH2:36][C@H:35]([N:40]([CH3:41])[CH3:42])[C@H:34]2[OH:43])[C@@:10]([OH:45])([CH3:44])[CH2:9][C@@H:8]([CH3:46])[C@H:7]([NH2:47])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CCOP(=O)(CC(OC)OC)OCC
Agent: CC[C@H]1OC(=O)[C@H](C)[C@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)[C@H](N)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: C1COCCO1
Solvent: O
Product: CCOP(=O)(CC=O)OCC
Temperature: 25 °C

Procedure:
A mixture consisting of 2.3 gm (0.003mol) of erythromycylamine, 1.4 gm (0.006 mol) of diethylphosphonoacetaldehyde-dimethylacetal, 20 ml of dioxane, 2 ml of water and 12 gm of Dowex W 50 was stirred at room temperature. After 6 hours of stirring the ion exchanger was filtered off and washed with dioxane. Water was added to the filtrate until crystallization started. The white product was suction-filtered off, washed with aqueous dioxane and dried. Yield: 1.4 gm (52% of theory), m.p. 110°-113° C (decomp.).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10](Cl)[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]=[C:15](/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11](=[O:12])[O:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C@@H:22]1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(Cl)C=O
Reactant: CCOC(=O)C(=O)/C=C/c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C[C@H](c2ccc(C)cc2)[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)O1
Yield: 83 %

Procedure:
Prepared according to the general procedure from 3-(tert-butyldimethylsilyloxy)-2-chloropropanal and (E)-ethyl 2-oxo-4-p-tolylbut-3-enoate using 2 mol % 1 as the catalyst in 83% yield as a single diastereomer (white solid). [α]D2 (c 1.27, CHCl3)=+244.6; mp=60-61° C.; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 3H), 7.12 (d, 2H, J=8.1 Hz), 6.99 (d, 2H, J=8.1 hz), 6.70 (d, 1H, J=7.5 Hz), 4.32 (q, 1H, J=7.2 Hz), 3.77 (t, 1H, J=6.8 Hz), 2.81 (q, 1H, J=6.8 Hz), 2.33 (s, 3H), 1.72-1.63 (m, 2H), 1.37-1.14 (m, 19H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 167.3, 160.7, 142.6, 138.2, 132.0, 129.8, 128.5, 118.9, 62.1, 58.7, 45.8, 38.3, 26.0, 21.3, 18.3, 14.4, −5.3, −5.4; IR (thin film) ν 3027, 2953, 2929, 2857, 1776, 1740, 1658, 1471, 1370, 1317, 1262, 1084 cm−1; HRMS (EI) calcd for C25H36O4 [M-Bu]+ 347.1315, found 347.1305; 95% ee (4S,5R)-isomer as determined by HPLC (AD-H, 100:1 hexanes/i-PrOH), tr (4S,5R)=8.5 min, tr (4R,5S)=10.0 min.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.Cl.CC[O:32]CC>ClCCl>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH:11]=[O:32]
Reactant: CCOCC
Reactant: N#Cc1cc2c(cc1I)CCC2
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cc2c(cc1I)CCC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 6-iodoindane-5-carbonitrile (36.5 mg, 0.136 mmol) in dichloromethane (1.0 mL) under N2 at −78° C. was added a solution of 1N DIBALH in toluene (272 μL, 0.272 mmol) dropwise. The reaction was stirred at −78° C. for 15 min. Keeping the temperature at −78° C., another two portions of DIBALH (100 μL each) were added until the starting material disappeared by TLC. The reaction mixture was poured into 2N HCl (45 mL) and diluted with Et2O. The mixture was stirred for 0.5 h. The Et2O layer was separated. The aqueous layer was extracted with Et2O (2×). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford 6-iodoindane-5-carbaldehyde (27 mg, 73%). 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H,), 2.19-2.13 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([CH:17]=2)[NH2:16])(=[O:10])=[O:9])[CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([NH:16][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1N
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1NC1CCN(C)CC1
Temperature: 27 °C
Reaction time: 4 h

Procedure:
5-(5-Bromo-2-methoxybenzenesulfonyl)-2-methoxyaniline (2 grams, 5.35 mmol) was added to 100 mL three necked round bottomed flask, followed by the addition of 1-methyl-4-piperidone (550 mg, 4.86 mmol), sodium sulfate (1.4 grams, 9.73 mmol) and acetic acid (40 mL) under nitrogen atmosphere. The reaction mass was stirred for 4 hours at room temperature (27° C.). Then sodium triacetoxy borohydride (3.08 grams, 14.60 mmol) was added to the reaction mass at 20-25° C. in 5 minutes. This reaction mixture was further stirred for another 2 hours at room temperature. The reaction mixture was then quenched into 100 mL water, basified to pH 9 with 50% aqueous sodium hydroxide solution under cooling (10° C.) and extracted the product with ethyl acetate (3×100 mL). The combined organic layer was washed with saturated brine solution (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain oily mass. The technical product was further purified by column chromatography using ethyl acetate and methanol as eluents to obtain the title product. Yield: 1.56 grams.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[S:21][C:20]4[N:22]=[CH:23][CH:24]=[N:25][C:19]=4[N:18]([CH2:26][O:27][CH3:28])[C:17]=3[CH:29]=2)[C:10]=1[CH3:11])=O)C.[NH3:30]>O1CCCC1>[CH3:28][O:27][CH2:26][N:18]1[C:17]2[CH:29]=[C:13]([CH2:12][N:9]3[C:10]([CH3:11])=[C:6]([C:4]([NH2:30])=[O:3])[N:7]=[CH:8]3)[CH:14]=[CH:15][C:16]=2[S:21][C:20]2[N:22]=[CH:23][CH:24]=[N:25][C:19]1=2
Reactant: N
Reactant: CCOC(=O)c1ncn(Cc2ccc3c(c2)N(COC)c2nccnc2S3)c1C
Solvent: C1CCOC1
Product: COCN1c2cc(Cn3cnc(C(N)=O)c3C)ccc2Sc2nccnc21
Temperature: 100 °C

Procedure:
To a solution of 0.7 g of ethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carboxylate in tetrahydrofuran (10 ml) was added 50 ml of aqueous ammonia. After sealing, the resulting mixture was heated to 100° C. for 24 hours.