Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:35]2[C:36]([C:41]3C=CC=CN=3)=[N:37]OC=2C)C=1)=O.C(N)(C)C>>[CH:36]([NH:37][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:41])[CH3:35]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)ns1
Solvent: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC(C)C)sn1
Yield: 68 %

Procedure:
As described for example 14e, 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (21 mg, 0.36 mmol), to the title compound (74 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=358.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-1-ethyl-1-pyrrolidin-3-yl-urea (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.16 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate/methanol (5%) to ethyl acetate/methanol (10%) to give the desired product as yellow solid. 1H-NMR (CDCl3) δ: 1.05 (3H, t), 1.40 (6H, s), 1.80 (1H, m), 2.20-2.40 (3H, m), 2.50-3.00 (8H, m), 3.40 (4H, q and m), 4.20 (1H, m), 5.20 (2H, br, s), 6.20 (1H, t), 6.65 (1H, d), 7.00 (2H, dd), 7.20-7.40 (5H, m), 7.70 (1H, dd), 8.50 (1H, dd) 9.80 (1H, br s). ESI-MS m/z: 561 (M+1), UV retention time: 1.45 min.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]=[O:9]
Reactant: OCC1CC2CCC1C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1CC2CCC1C2
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A stirred suspension of 2-norbornylmethanol (0.5 ml; 5.8 mmol) and PCC on Al2O3* in CH2Cl2 (25 ml) was stirred at 2-3° C. for 1 h and allowed to slowly warm up to rt. The reaction mixture was filtered and the solid material washed with CH2Cl2 (2×25 ml). The combined organic fractions were adsorbed onto silica and chromatographed to give 300 mg (42%) product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: [H][H]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(O)ccc1OCC(=O)OCC
Yield: 57.3 %

Procedure:
A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60 g, 1.83 mmol) in THF (15 mL) was treated with 5% Pd/C (75 mg) and hydrogen (60 psi) at ambient temperature for 24 h. The mixture was filtered and concentrated. The crude product was purified by radial chromatography using 15% ethyl acetate in hexanes to give a tan solid (0.25 g, 57%). 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239 (M+1).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[CH2:6][CH2:5]2)OC1.[ClH:18].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH2:24])=[NH:23]>C(#N)C>[ClH:18].[F:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:20]2[C:21]=1[C:22]([NH2:24])=[N:23][C:4]1([CH2:5][CH2:6][N:7]([C:10]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)=[O:11])[CH2:8][CH2:9]1)[NH:19]2
Reactant: N=C(N)c1c(N)cccc1F
Reactant: O=C(N1CCCC1)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: NC1=NC2(CCN(C(=O)N3CCCC3)CC2)Nc2cccc(F)c21
Yield: 29.9 %

Procedure:
1-(1-pyrrolidinylcarbonyl)-4-piperidone ethylene ketal (120 mg, 0.5 mmol) and 2-amino-6-fluorobenzamidine hydrochloride (113 mg, 0.5 mmol) in dry acetonitrile (10 ml) were heated at reflux for 18 h. The mixture was cooled and filtered and the filtrate treated with an equal volume of dry ether. After standing in the refrigerator overnight the pale yellow solid which separated was filtered, washed with dry ether and dried to give the title compound (55 mg), m.p. 246°-248° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](OC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[OH:14][CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc2ccccc2c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(CO)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
The product of Step A (4.5 g, 20.83 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to 0° C. To this solution was added a 1 M solution of lithium aluminum hydride in tetrahydrofuran (31 mL). The mixture was stirred at this temperature for 30 min, allowed to warm up to room temperature, and stirred for an additional 30 min. Ethyl acetate (200 mL) was then added carefully to the reaction mixture to destroy the excess of lithium aluminum hydride. The mixture was then diluted with a 1 M solution of aqueous hydrogen chloride (100 mL), the organic layer was separated, dried (MgSO4), and concentrated to give an oil (4.1 g) which solidified: 1H NMR (CDCl3) δ 3.97 (s, 3H, CH3), 4.89 (s, 2H, CH2), 7.51 (m, 3H, Ar—H), 7.60 (m, 1H, Ar—H), 7.82 (m, 1H, Ar—H), 8.07 (m, 1H, Ar—H); MS (GC/MS) 188.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:5]([CH2:4][CH2:3][C:2]([F:20])([F:21])[F:1])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(CCC(F)(F)F)C(=O)OC(C)(C)C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(CCC(F)(F)F)c1ccc(CBr)cc1

Procedure:
540 mg (1.79 mmol) of tert-butyl 5,5,5-trifluoro-2-(4-methylphenyl)pentanoate, 333.8 mg (1.78 mmol) of N-bromosuccinimide and 14.7 mg (0.09 mmol) of 2,2′-azobis-2-methylpropionitrile in 10 ml of carbon tetrachloride were stirred under reflux for 2 h. After the reaction had gone to completion, the succinimide was filtered off and the filter residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 659 mg (1.72 mmol, 97% of theory) of a yellowish oil.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([C@H:39]([CH3:62])[C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:51][CH:50]=1)[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:10]([C@@H:12]1[CH2:16][O:15][C:14]([C:28]([O:30][CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:29])([C:17]([O:19][CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[O:13]1)=[O:11])=[O:7])(C)(C)C>C(O)=O>[C:6]([CH2:8][N:9]([C@H:39]([CH3:62])[C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:51][CH:50]=1)[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:10]([C@@H:12]1[CH2:16][O:15][C:14]([C:28]([O:30][CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])=[O:29])([C:17]([O:19][CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])=[O:18])[O:13]1)=[O:11])([OH:7])=[O:5]
Reactant: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)OC(C)(C)C)C(=O)[C@@H]1COC(C(=O)OCOC(=O)C(C)(C)C)(C(=O)OCOC(=O)C(C)(C)C)O1
Solvent: O=CO
Product: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)O)C(=O)[C@@H]1COC(C(=O)OCOC(=O)C(C)(C)C)(C(=O)OCOC(=O)C(C)(C)C)O1
Reaction time: 2 h
Yield: 85 %

Procedure:
926 mg of 2,2-bis(pivaloyloxymethyl) (4S)-4-[N-(tert-butoxycarbonylmethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoyl]-1,3-dioxolane-2,2-dicarboxylate was dissolved in 12 ml of formic acid and left to stand at room temperature for 2 hours. Then, formic acid was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→1/1) to obtain 723 mg (yield: 85%) of the above identified compound as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccnc(Br)c1
Product: COC(=O)c1ccnc(-c2ccccc2Cl)c1

Procedure:
500 mg (2.31 mmol) of methyl 2-bromoisonicotinate and 597 mg (3.47 mmol) of 2-chlorophenylboronic acid were reacted with one another analogously to the process of Example 58A. This gave 323 mg (56% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14][CH2:15][C:16]#N)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)[C:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([O:14][CH2:15][C:16]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCC#N)c1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
A mixture of cyanomethyl 3-(t-butyloxycarbonylamino)benzoate (20 g), triethylamine (10.6 g), 4-dimethylaminopyridine (0.1 g) and benzyl alcohol (11.4 g) is stirred at a bath temperature of 55° C. for 15 hours. The reaction mixture is extracted with ethyl acetate (200 ml), and the extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 80% aqueous acetonitrile solution to give the title compound (22.0 g, 93%) as white short needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].F[C:21]1[CH:22]=[N+:23]([O-:30])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:21]2[CH:22]=[N+:23]([O-:30])[CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: COc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c[n+]([O-])ccc2[N+](=O)[O-])c2ccccc12
Reaction time: 0.25 h

Procedure:
To a solution of 4-methoxy-1-naphthol (8.87 g) in 50 ml of DMF was added sodium carbonate (7.8 g) portionwise, and after the addition was complete the mixture was stirred for 15 minutes. Then a solution of 3-fluoro-4-nitropyridine-N-oxide (8.0 g) in 50 ml DMF was added dropwise at room temperature. The reaction was then allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with NaCl (sat) and dried (anhy. MgSO4).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([OH:8])=[O:7].S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>C(C(C)=O)C.O>[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([O:8][CH3:21])=[O:7]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Yield: 93 %

Procedure:
A reaction vessel is charged in succession with 360 g of water, 475 g of methyl ethyl ketone and 307 g (1.0 mole) of the sodium salt (dry) of 3,4,5,6-tetrachloro-2-cyanobenzoic acid. With stirring, the mixture is heated to 72°-74° C. and to the suspension so obtained are added, at this temperature and over 1 hour, 189 g of dimethyl sulfate (1.5 moles), while keeping the pH at 5.0-5.5 by the gradual addition of 66 g (0.5 mole) of 30% sodium hydroxide solution. The reaction mixture is then stirred for 1 hour at reflux temperature (72°-74° C.). Conventional working up affords a yield of 93% of theory of methyl 3,4,5,6-tetrachloro-2-cyanobenzoate, based on the sodium salt of 3,4,5,6-tetrachloro-2-cyanobenzoic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7]CC)=[O:6].[Li+].[OH-].O>CO>[F:1][C:2]([F:12])([F:13])[CH2:3][C:4]([CH3:10])([CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(C)CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CC(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of ethyl 4,4,4-trifluoro-2,2-dimethylbutanoate (426 mg, 2.15 mmol) in MeOH (15 mL) was added a solution of LiOH in H2O (2 N, 5.35 mL, 10.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated and the resulting mixture was diluted with DCM and washed with 3 N HCl. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield 4,4,4-trifluoro-2,2-dimethylbutanoic acid as a colorless oil (370 mg, 100% yield). 1H NMR (400 MHz, CDCl3) ppm 1.35 (s, 6H), 2.48 (ABqt, J=12 Hz, 2H).
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][C:1](=[O:11])[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH2:3])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: C=C(C(=O)O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: C=C(C(=O)NC1CCCCC1)c1ccccc1
Yield: 28.9 %

Procedure:
This compound was made from atropic acid (10.48 g, 70.8 mmol), N-methylmorpholine (7.8 ml, 70.9 mmol), iso-butyl chloroformate (9.2 ml, 70.9 mmol), and cyclohexylamine (8.1 ml, 70.7 mmol) using the procedure described in Example 3. The crude product was purified by recrystallisation from cyclohexane to give the product (4.69 g), as white crystals, m.p. 131°-133°.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[NH2:5][C:6]1[NH:11][C:10](=[O:12])[CH:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1>CCO>[NH2:5][C:6]1[N:11]([CH3:3])[C:10](=[O:12])[CH:9]=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1
Reactant: Nc1nc(-c2ccccc2)cc(=O)[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)nc(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of KOH (1.22 g, 22 mmol), MeI (6.85 g, 48 mmol), and 2-amino-6-phenyl-3H-pyrimidin-4-one (2.62 g, 14 mmol) in EtOH (130 mL) was stirred at room temperature in a stoppered 250 mL roundbottom flask for 3 days. An additional 6.85 g (48 mmol) MeI was added and stirring was continued for 1 day. The solvent was removed under vacuum and the residue was dissolved in H2O (35mL), warmed to 50° C., and 1N HCl was added dropwise until the solid dissolved completely. The solution was cooled to room temperature, made slightly basic with saturated NaHCO3, and the resulting white solid was filtered and dried under vacuum. M+1: 202.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide (10.0 g, 0.027 mol) in methanol (150 mL) containing anhydrous ammonia (2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in the presence of a slurry of Raney nickel A-7000 (3.8 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.5 g of (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide as an oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O)(C)(C)C.Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[NH2:8])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccsc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
Treat dropwise a solution of (tert-butoxy)-N-[2-(4-bromophenyl)(3-thiophenyl)]carboxamide (10.8 g, 0.3 mol) in EtOAc (75 mL) at 0° C. with 244 mL (8 mL/mmol) of freshly prepared 1N HCl in EtOAc and stir the mixture at room temperature overnight. Dissolve the white precipitate with H2O (100 mL) and neutralize with a NaHCO3 saturated solution. Extract the mixture with EtOAc (3×100 mL) and combine organic, dry and concentrate to give a slightly colored solid. Purification of the crude material by flash chromatography (Silica gel-Hexane/AcOEt 49:1 then 9:1) furnishes 5.7 g (74%) of 2-(4-bromo-phenyl)-thiophen-3-yl amine as a pale yellow solid.
Reaction SMILES: CC([O:5][C:6](=[O:29])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8]([O:10]C(C)(C)C)=[O:9])(C)C.CC([O-])(C)C.[K+].[C:36]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:39])[CH:37]=[CH2:38].CC(O)=O>CC(O)(C)C>[CH2:41]([O:40][C:36](=[O:39])[CH2:37][CH2:38][C:7]([C:8]([OH:10])=[O:9])([C:6]([OH:5])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C=CC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCC(CCC(=O)OCc1ccccc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a solution of di-(dimethylethyl)-n-tetradecylmalonate 34 (4.12 g, 10.0 mmol) and t-BuOK (244 mg, 2.0 mmol) in t-BuOH (10 mL, dried over 4 Å sieves) was added a solution of benzyl acrylate (1.62 g, 10.0 mmol in 5 mL t-BuOH). The initially colorless solution immediately turned brown. It was stirred (3 h, rt) then additional t-BuOK (112 mg, 1.0 mmol) was added and the reaction continued overnight. The mixture was neutralized with AcOH then evaporated to dryness and treated with neat TFA (20 mL, 1 h). The TFA was removed by rotary evaporation, the residue dissolved in warm hexane, treated with activated charcoal then filtered. The filtrate provided fine white crystals which proved to be pasty when filtered. Drying provided product 36 as a white solid (2.31 g, 50%), mp 47°-49° C. High resolution FAB MS:C27H43O6 (M+H); Theor. 463.307147. Found 463.3059 646. Anal. C27H42O6.1/2H2O:C,H.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:18]([CH:20]2[CH2:25][CH2:24][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
The compound obtained in Example 2 (252 mg, 0.60 mmol) and triethylamine (0.201 ml) were dissolved in THF (5 ml), and under ice cooling, to the solution was added methanesulfonyl chloride (0.093 ml). The mixture was stirred at the same temperature for 1 hour. The compound obtained in Example 2 (252 mg, 0.60 mmol) and triethylamine (0.201 ml) were dissolved in THF (5 ml). To the solution was added methanesulfonyl chloride (0.093 ml) under ice cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added diisopropyl ether (10 ml), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether, and dried under reduced pressure to give the titled compound,(110 mg, 0.22 mmol, Yield 37%) as white crystals.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl[C:9](Cl)([O:11][C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.C(Cl)Cl.CO>C(Cl)Cl>[NH2:3][CH2:6][CH2:7][CH:9]1[CH2:14][O:13][C:12](=[O:18])[O:11]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: NCCC1COC(=O)O1
Yield: 263.2 %

Procedure:
To a solution of the diol (9 g, 37.66 mmol) in CH2Cl2 (200 mL) was added triethylamine (15.2 g, 151 mmol) at −20˜30° C. under N2. After several minutes, triphosgene (5.5 g, 18.83 mmol) was added to the mixture dropwise at this temperature and stirred at −20˜30° C. for half an hour. Then the mixture was stirred at room temperature for 15 h. TLC (CH2Cl2/MeOH=10:1) showed the starting material was almost consumed. To the mixture was added water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified through silica gel chromatography (CH2Cl2/MeOH=10:1) to give the corresponding cyclized dioxolane (6.5 g, 55%) as pale solid.