Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[Br:26][C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[N:35]([CH2:43]S(C1C=CC=CC=1)(=O)=O)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>O>[Br:26][C:27]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=1[N:35]([CH2:43][C:13]1[C:14](=[O:17])[CH2:15][CH2:16][C:12]=1[NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:18])([F:19])[F:3])[CH:6]=1)[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41]
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 360 mg, 9.00 mmol) is added in portions to a mixture of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (2.16 g, 8.96 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (2-bromo-4-cyanophenyl)(phenyl-sulfonyl)methylcarbamate (Step 1, 3.35 g, 7.43 mmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue is treated with tert-butyl methyl ether, and the mixture is stirred for 15 min. The precipitate is filtered, washed with tert-butyl methyl ether, and dried. Yield: 3.18 g. ESI mass spectrum: [(79Br)-M+H]+=550, [(81Br)-M+H]+=552; Retention time HPLC: 0.73 min (X012_S01).
Reaction SMILES: C(N1C2C=CC=CC=2N([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)C1=O)(C)C.[CH2:31]([O:33][C:34]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]1=[O:45])=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:37]1=[O:45])=[O:35])[CH3:32]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Product: CCOC(=O)n1c(=O)n(Cc2nc3cc(C#N)ccc3n2CCC(C)C)c2ccccc21

Procedure:
3-[5-Cyano-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid ethyl ester was prepared by the same procedure as 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile, except using 2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid ethyl ester (N. Meanwell et al, J. Org. Chem, 1995, 60(6), 1565-82) and was used without purification in the next reaction.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[O:19][CH:20]=2)[CH:14]=1.C(C#N)(C)=[O:29]>O=[Mn]=O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:29])[OH:22])[O:19][CH:20]=2)[CH:14]=1
Reactant: O=C(Nc1cnn(Cc2coc(CO)n2)c1)OCc1ccccc1Cl
Reactant: CC(=O)C#N
Agent: O=[Mn]=O
Agent: N#N
Product: O=C(Nc1cnn(Cc2coc(C(O)O)n2)c1)OCc1ccccc1Cl
Temperature: 55 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-hydroxymethyl-oxazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (238 mg, 0.65 mmol) in AcCN (5.0 mL) was treated at rt with MnO2 (317 mg, 3.28 mmol) and the reaction mixture was stirred at 55° C. for 4 h before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a brown oil. TLC: rf (EA)=0.48. LC-MS-conditions 02: tR=0.81 min; [M+H]+=379.22.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:13]#[N:14].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4][C:13]#[N:14]
Reactant: COc1ccc(CBr)c(Cl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CC#N)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
With stirring, a solution of 68 g of 2,3-dichloro-4-methoxybenzyl bromide in 220 ml of dimethyl sulfoxide was added dropwise to a suspension of 15 g of anhydrous sodium cyanide in 250 ml of anhydrous dimethyl sulfoxide. The mixture was subsequently heated to reflux temperature under an atmosphere of nitrogen for 5 hours. The cold reaction mixture was poured into 1.5 l of ice-water, after which the solid product which had formed was separated off, washed with water and purified by trituration with petroleum ether (at 40—60° C). Yield: 51 g (white crystals); m.p.: 118—119° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12].C(N(CC)C(C)C)(C)C.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](Cl)=[O:35]>C(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[C:3]([CH:8]=1)[CH2:2][NH:1][C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=1)=[O:35]
Reactant: O=C(Cl)c1ccccn1
Reactant: NCc1cc(Br)ccc1NC(=O)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cc(Br)ccc1NC(=O)c1ccccn1)c1ccccn1
Yield: 69.9 %

Procedure:
Compound 2-3 (0.050 g, 0.16 mmoles) was dissolved in 6 mL of methylene chloride. To the reaction vessel was added (0.06 mL, 0.32 mmoles) of N,N-diisopropylethylamine and (200 mg, 0.32 mmols, 1.49 mmol/gram) followed by the addition of (0.057 g, 0.32 mmol) picolinoyl chloride. The mixture was stirred until complete by TLC. The compound was then filtered and then the solvent was removed and then purified on a mass guided LC/MS to provide 46 mg (70%) of the title compound. 1H NMR (300 MHz, CDCl3): 8.89 ppm (s, 2H), 8.43 ppm (m, 2H), 8.22 ppm (m, 2H), 8.13 ppm (t, J=4 Hz, 1H), 8.0 ppm (s, 1H), 7.81 ppm (m, 2H), 7.41 ppm (m, 1H), 7.2 ppm (m, 2H), 4.22 ppm (d, J=4 Hz, 2H); HRMS calc'd for C19H15BrN4O2 (M+1) 411.0451; Found: 411.0444
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:15]([OH:17])=[O:16])[CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 24 h

Procedure:
A solution of the compound of example 69 (2.29 g, 6.54 mmol) in ethanol (95%, 500 mL) was hydrogenated in the presence of a catalytic amount of palladium (10% on charcoal). After 24 h of stirring, the reaction was complete. The mixture was filtered over a celite pad and the solvent evaporated. The residue was distributed between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The product was sufficiently pure on the basis of its 1H-NMR spectrum to be used in the next step. 1H-NMR(CDCl3, 400 MH: 1.23(t, J=7.1, 3H); 1.41(s, 9H); 2.53–2.81(m, 4H); 3.25(m, 1H); 4.13(m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>C1COCC1.CN(C)C1C=CN=CC=1>[O:23]=[C:15]1[C:14](=[C:10]2[C:11]3[C:7](=[CH:6][C:5]([NH:4][CH2:3][CH2:2][O:1][C:24](=[O:26])[CH3:25])=[CH:13][CH:12]=3)[CH2:8][O:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(NCCO)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a stirred mixture of 3-[5-(2-hydroxy-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (50 mg, 0.16 mmol) and acetic anhydride (20 mg, 0.20 mmol) in THF (3 ml), was added 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was stirred for 30 minutes and was then poured into water (75 ml). The solid was filtered, washed with water and dried under vacuum to give acetic acid 2-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-ylamino]-ethyl ester as a yellow solid (39 mg, 68%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:22][CH2:21][C@:20]2([O:23][CH3:24])[C@:11]34[CH2:27][CH2:26][N:25]([CH3:28])[C@@H:19]2[CH2:18][C:17]2[CH:16]=[CH:15][C:14]([OH:29])=[C:13]([O:30][C@@H:10]13)[C:12]4=2)C1C=CC=CC=1.C1CCCCC=1>[Pd].CO>[NH2:8][C@@H:9]1[CH2:22][CH2:21][C@:20]2([O:23][CH3:24])[C@:11]34[CH2:27][CH2:26][N:25]([CH3:28])[C@@H:19]2[CH2:18][C:17]2[CH:16]=[CH:15][C:14]([OH:29])=[C:13]([O:30][C@@H:10]13)[C:12]4=2
Reactant: CO[C@@]12CC[C@@H](N(Cc3ccccc3)Cc3ccccc3)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: CO[C@@]12CC[C@@H](N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5

Procedure:
A mixture of Compound 14 (1.02 g, 2.05 mmol), 10% Pd/C catalyst (0.52 g), cyclohexene (30 ml) and absolute MeOH (30 ml) were reflux heated for 16 hours under N2. Then the catalyst was filtered off and the filtrate evaporated. The residue (0.66 g of white foam resin) was crystallised out of i-PrOH/Et2O 1:1 (2 ml). Yield: 0.33 g (42%) of beige crystals: Fp>235-239° C.; IR (KBr): 3348 (OH) cm−1; 1H-NMR (CDCl3): 6.62 (d, J=8.0, 1 arom. H); 6.54 (d, J=8.0, 1 arom. H); 4.26 (d, J=7.0, H—C(5)); 3.22 (s, CH3O—C(14)); 2.36 (s, CH3N); Cl-MS: m/z 317 (M++1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:19]1[CH:20]=[C:21]([F:30])[C:22]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[N:23][CH:24]=1>>[CH:27]1([CH2:26][O:25][C:22]2[N:23]=[CH:24][C:19]([C:2]3[O:1][C:5]4[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:20][C:21]=2[F:30])[CH2:28][CH2:29]1
Reactant: Fc1cc(Br)cnc1OCC1CC1
Reactant: CC(=O)N[C@@H](C)COc1ccc2ncoc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cnc(OCC4CC4)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-(1,3-benzoxazol-6-yloxy)propan-2-yl)acetamide and 5-bromo-2-(cyclopropylmethoxy)-3-fluoropyridine, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[N:13]=[C:14]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:22])[S:15][C:16]=1[C:17](O)=[O:18]>>[CH3:11][C:12]1[N:13]=[C:14]([NH:20][C:21](=[O:22])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[S:15][C:16]=1[C:17](=[O:18])[NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCCCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 3-phenylpropylamine in place of benzylamine to react with 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid, the title compound was obtained as a white solid in 22% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.78-8.76 (m, 2H), 8.13-7.93 (m, 3H), 7.27-7.11 (m, 5H), 3.32-3.11 (m, 2H), 2.70-2.46 (m, 5H), 1.84-1.72 (m, 2H); MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([OH:40])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc2[nH]1

Procedure:
To a r.t. solution of (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-phenylpiperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (77 mg, 0.131 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction was concentrated after 4 hours and diluted with ethyl acetate and saturated aqueous NaHCO3. This mixture was then extracted with ethyl acetate, and the combined the organic layers were washed with brine, dried over Na2SO4, and concentrated. This material was then purified via reverse phase HPLC on a 19×50 mm Waters Sunfire C18 column (5μ particle size) using a linear gradient with acetonitrile/water and buffering with 0.16% TFA at a flow rate 25 mL/min. The desired fractions were concentrated to obtain the title compound as a white sticky solid. LC-MS: calculated for C23H25ClN4O4 456.16 observed m/e: 457.33 (M+H)+ (Rt 1.08/2 min). 1H NMR δ (ppm) (DMSO): 7.76 (s, 1H), 7.30-7.28 (m, 4H), 7.19 (m, 1H), 5.38 (q, 1H), 4.80 (t, 1H), 4.33 (t, 1H), 4.14-4.09 (m, 2H), 3.85 (m, 1H), 3.74 (m, 1H), 3.59 (d, 2H), 3.40 (t, 1H), 2.85 (t, 2H), 2.68 (m, 1H), 1.85 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=CCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCCOc1ccc(CCCCCC(=O)O)cc1
Yield: 94.2 %

Procedure:
This compound was synthesized from 6-(p-butoxyphenyl)-5-hexenoic acid (2.62 g, 10 mmol) by a hydrogenation reaction using Pd/C (260 mg). Crystallization (petroleum ether) afforded the product (2.49 g, 94%) as white crystals (mp 39°-40° C.). IR: 3400=2500, 1705 cm-1 ; 1H-NMR: 0.96 (t, 3H), 1.35 (m, 2H), 1.50 (m, 2H), 1.62 (m, 4H), 1.75 (m, 2H), 2.35 (t, 2H), 2.52 (t, 2H), 3.92 (t, 2H), 6.95 (q, 4H), 10.30 (bs, 1H). Anal. Calcd. for C16H24 O3 : C, 72.69, H, 9.15%; Found: C, 72.78, H, 9.18%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][OH:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[O:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 g 2-Chloro-4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile were suspended in 50 ml dichloromethane and cooled in an ice bath. 0.39 ml methanesulfonylchloride and 0.89 ml triethylamine were added. The resulting mixture was stirred at 0° C. for one hour then washed with water and brine, dried over MgSO4. The solvent was removed in vacuo to obtain 1.0 g methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1.O.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c(F)cc1SC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(F)c(C2CCN(C(=O)OCc3ccccc3)CC2)cc1C(=O)O
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 4-(2-fluoro-4-methylthio-5-methoxycarbonylphenyl)-N-Cbz-piperidine (1.38 g) dissolved in 100 mL 1:1 THF:H2O was added 0.45 g LiOH. Mixture was stirred for 18 h, THF was evaporated, residue was mixed with 25 mL 1N HCl, and extracted with DCM (3×50 mL). Extracts were combined, dried over Na2SO4, and evaporated to give 1.33 g product; MS m/z 404 (M+H); 1H NMR (CDCl3) δ 8.01 (d), 7.45-7.25 (m), 6.94 (d), 5.17 (s), 4.50-4.21 (m), 2.99 (tt), 3.01-2.78 (m), 2.44 (s), 1.84 (dm), 1.69 (qd).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1
Reactant: CCCCCCCBr
Reactant: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Product: CCCCCCCOc1ccc(F)cc1C(C)(O)Cn1ccnc1
Yield: 94.3 %

Procedure:
The general procedure of Example 6 was repeated using 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-4)] and n-heptyl bromide, to thereby yield 2-(5-fluoro-2-(n-heptyloxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as colorless crystals (yield: 94.3%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].Cl[P:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(N(CC)CC)C.C1C=CC=CC=1>[C:18]1([P:17]([O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 42.4 grams of 2,4-di-tert-butylphenol in 101 grams of triethylamine was added dropwise over a 15-minute period 17.9 grams of dichlorophenylphosphine. The reaction mixwas then heated for 6 hours at 65°-70° C. After cooling to room temperature, the reaction mixture was diluted with 50 ml of benzene and poured onto a rapidly stirred mixture of 70 grams of concentrated hydrochloric acid and 200 grams of chopped ice. The product was then isolated as in Example 17 with the product crystallized from acetonitrile as white crystals melting at 90°-93° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[C:11]([CH2:14]Br)[C:10]=2[CH:16]=1>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[C:11]([CH2:14][C:1]#[N:2])[C:10]=2[CH:16]=1
Reactant: BrCc1csc2ccc(Br)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1csc2ccc(Br)cc12
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of 0.115 gm (2.34 mMol) sodium cyanide, 2 mL ethanol and 1 mL water was heated to reflux. To this refluxing mixture was added a solution of 0.356 gm (1.16 mMol) 5-bromo-3-(bromomethyl)benzothiophene in 4 mL ethanol. The resulting mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 10% dichloromethane and 5% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.214 gm (73%) of the desired nitrile as a solid.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=1.C(N(C(C)C)CC)(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][CH:18]([C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=[C:10]([NH:9][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:11]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=1)#[N:32]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Reactant: O=C(Cl)C1CCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(NC(=O)C2CCCC2)c1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
Cyclopentanecarbonyl chloride (0.104 ml, 0.85 mmol) was added dropwise at 0° C. to a solution of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (250 mg, 0.772 mmol) obtained in Example 223.4 and diisopropylethylamine (0.146 ml, 0.85 mmol) in CH2Cl2 (5 ml). The reaction mixture was warmed slowly (2 h.) to room temperature. A saturated aqueous solution of KHSO4 was added and the mixture was extracted with EtOAc. The organic phase was washed with H2O, dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexanehexane/EtOAc 2:1). There were obtained 215 mg (66%) of ethyl (RS)-(4-cyano-phenylamino)-[3-(cyclopentanecarbonyl-amino)-5-ethyl-phenyl]-acetate as a colorless foam; MS: 418 ([M−H]−).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Cl[Sn](Cl)(Cl)Cl.[I:16]I>ClCCl>[I:16][CH2:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10]1
Reactant: II
Reactant: C=CCc1ccccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: ICC1Cc2ccccc2O1
Reaction time: 5.5 h
Yield: 35.9 %

Procedure:
To a solution of 2-allylphenol (10 g, 75 mmol) in dichloromethane (150 ml) was added SnCl4 (29.7 g, 37.3 mmol, 0.5 eq) and iodine (19 g, 75 mmol, 1 eq) at room temperature. After stirring for 5.5 hours, the reaction mixture was diluted with additional dichloromethane (200 ml) and then quenched with water (200 ml). The organic layer was separated and the aqueous layer was adjusted pH to ˜8 with sodium bicarbonate and then extracted with dichloromethane (3×150 ml). The organic layers were combined, washed with 5% aqueous Na2S2O4 (200 ml), dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by silica gel chromatography using with 0.5-1% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated to afford 2-(iodomethyl)-2,3-dihydro-1-benzofuran as brown oil (7 g, 36%); 1H NMR (300 MHz, CDCl3): δ 7.09-7.17 (m, 2H), 6.74-6.89 (m, 2H), 4.84-4.93 (m, 1H), 3.30-3.47 (m, 3H), 3.00-3.08 (m, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]1[CH:7]([CH2:8][O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:6][CH:7]([OH:5])[CH2:8][O:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1
Reactant: NCCO
Reactant: c1csc(OCC2CO2)n1
Solvent: CCO
Product: OCCNCC(O)COc1nccs1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I of the invention. In this example 0.6 g. of ethanolamine is added to a solution of 0.3 g. of 1,2-epoxy-3-(thiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of 1,2-epoxy-3-(thiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-(β-hydroxyethylamino)-3-(thiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography.