Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>C(O)(=O)C>[ClH:22].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([O:20][CH3:21])=[O:19])[CH2:10]1
Reactant: COC(=O)c1cccc2c1CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1CC(N)C2

Procedure:
Using 2-(tert-butoxycarbonylamino)-4-methoxycarbonylindan (45 mg, 0.15 mmol) synthesized in the above Preparation Example 7, 4N hydrochloric acid-dioxane (0.7 ml) and acetic acid (2.1 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-4-methoxycarbonylindan hydrochloride. Then, using the 2-amino-4-methoxycarbonylindan hydrochloride, 4-chloro-5-methylthieno[2,3-d]pyrimidine (28 mg, 0.15 mmol), triethylamine (63 μl, 0.45 mmol), and ethanol (1 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (15 mg, 0.044 mmol) having the following physical properties:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8].[N+:16]([O-])([OH:18])=[O:17]>>[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To 15 mL of concentrated sulfuric acid at 0° C. is added 6.9 g (0.05 mmol) of 4-fluoroacetophenone. To the resulting solution is rapidly added a mixture of 4 mL nitric acid and 6 mL concentrated sulfuric acid. The reaction mixture is stirred at 0-5° C. for 3 hours. The reaction mixture is then poured into ice water, and the resulting mixture is extracted with chloroform. The combined organic fractions are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified using column chromatography on silica gel, eluting with 20% ethyl acetate/hexanes, yielding 6.0 g of 4-fluoro-3-nitroacetophenone (60% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c2cc1OC
Yield: 58 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from the previous step (114 mg, 0.42 mmol) using Example 115C. The final product was purified by silica gel column chromatography (25-100% EtOAc/hexanes) to give 1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (83 mg, 0.18 mmol, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.50-7.36 (m, 3H), 7.31-7.14 (m, 3H), 7.05-6.86 (m, 2H), 4.00 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 473 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].[OH-:22].[NH4+].Cl>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:5]([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:22]
Reactant: [OH-]
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Yield: 56.3 %

Procedure:
To a 250 mL flask was charged 38.16 g (0.119 mole) of alpha-n-butyl-alpha(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-propanenitrile followed by 100 mL (0.63 moles) of 48% hydrobromic add. The mixture was stirred at reflux for 48 hours after which GLC indicated disappearance of the starting material. The reaction was cooled to room temperature and neutralized with concentrated ammonium hydroxide (100 mL) to pH 8 and then to neutral pH with concentrated hydrochloric acid. A gummy oil formed which was diluted with 200 mL of ethyl acetate. The organic phase (3×200 mL ethyl acetate) was washed with 100 mL of water (3×). The organic phase was dried and concentrated to give a tan solid which was recrystallized from ethyl ether. The product was filtered and gave 22.78 g (56.3% yield) of a solid, melting point 170°-172° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=O)[S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>CCCCCC>[C:1]([C:9]1[CH:10]=[C:11](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])[S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1csc(C=O)c1
Reactant: O=C(O)CC(=O)O
Solvent: CCCCCC
Product: CCCCCCC#Cc1csc(/C=C/C(=O)O)c1
Yield: 91 %

Procedure:
Reaction of 4-(1-octynyl)-2-thiophenecarboxaldehyde (1.1 g, 5 mmole) with malonic acid by the method described in Example 2 yielded the title compound 1.19 g, (91%) as a fawn solid, mp 81° (hexane) νmax (mull) 2600(vb) 1695, 1680, 1625, 965, 940, 830, 760; δ(CDCl3) 0.90(3H, t, J=6 Hz), 1.4(8H, m), 2.37(t, 2H, J=6 Hz), 6.22(H, d, 15 Hz), 7.25(1H, s), 7.40(1H, s), 7.80(d, 1H, J=15 Hz), 11.5(1H, bs).
Reaction SMILES: Br[C@@:2]1([N:28]2[CH2:36][C:34]([CH:37]([O:44][CH3:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH:7]([CH:9]([O:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[C@@:4]([CH:19]([O:26][CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:5])[CH2:3]1.[O-:46][CH2:47][CH3:48].[Na+].Cl>C(O)C>[CH2:47]([O:46][C@@:2]1([N:28]2[CH2:36][C:34]([CH:37]([O:44][CH3:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH:7]([CH:9]([O:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[C@@:4]([CH:19]([O:26][CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:5])[CH2:3]1)[CH3:48]
Reactant: CC[O-]
Reactant: COC(c1ccccc1)C(O)[C@H]1O[C@@](Br)(N2CC(C)(C(OC)c3ccccc3)C(=O)NC2=O)C[C@@]1(O)C(OC)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCO[C@]1(N2CC(C)(C(OC)c3ccccc3)C(=O)NC2=O)C[C@@](O)(C(OC)c2ccccc2)[C@@H](C(O)C(OC)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1′-bromo-3′, 5′, 5-tris(methoxybenzyl)thymidine in ethanol is added to a stirred solution of sodium ethoxide in ethanol at −10° C. The resulting reaction mixture is stirred at room temperature fro 1 h, neutralized with dilute hydrochloric acid. Ethanol is evaporated and the remaining mixture extracted with ethyl acetate. The crude is purified by chromatography to give a mixture of α and β diasteriomers.
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]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[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])[CH:19]([OH: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]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)C(O)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (108 mg, 0.135 mmol) in 4 ml MeOH cooled to -5° C. (ice/acetone bath) was added in several portions NaBH3CN (160 mg). After addition was complete reaction was allowed to warm to RT. After stirring at RT for 2 hours the reaction mixture was diluted with 10 ml CH2Cl2 and purified by prep TLC (5% MeOH/CH2Cl2) to give the title compound (with NMR and mass spectra consistent with the structure).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([CH2:28][NH2:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH2:28][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([F:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1cnc(OCC(F)(F)F)c(F)c1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)(F)F)c(F)c1
Yield: 46 %

Procedure:
The title compound is prepared in 46% yield (98 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-22) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NCc1ccccc1
Yield: 43.8 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (120 mg, 0.32 mmol) obtained in Example 18 was dissolved in THF (10 mL), and benzylamine (102.87 mg, 0.11 mL, 0.93 mmol) and sodium iodide (9.60 mg, 0.06 mmol) were added thereto, followed by refluxing for 6 hrs. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 56 mg of the titled compound (yield: 44%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:29])[C@H:18]([NH2:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]([O-])(O)=[O:31].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:29])[C@H:18]([N:28]=[C:30]=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@@H](N)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C[C@@H](N=C=O)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
1-[2-(R)-Amino-3-(4-methoxyphenyl)-propionyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester hydrochloride (2.8 g) was dissolved in 30 mL of dichloromethane followed by addition of 30 mL of NaHCO3 solution (1M) under vigorous stirring. Triphosgene (0.6 g) in 6 mL of dichloromethane was added at 0° C. and the mixture was kept stirring for 0.25 h. The organic layer was separated and the solvent removed in vacuo to yield 1.20 g (98%) of the title compound as a yellow oil. (+)-APCI-MS: 409 (MH+).
Reaction SMILES: [Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a stirred solution of benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (2.8 g, 0.0059 mol) in methylene chloride (12 ml) were added dimethylamine hydrochloride (1.44 g, 0.0176 mol), formaldehyde (0.61 g, 0.020 mol) and t-butyl alcohol (100 ml), the mixture was heated to reflux at 95° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography with a solvent gradient of 10 to 25% ethyl acetate/hexane to afford benzhydryl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate-1, 1-dioxide (2.0 g, 69.5%) as a white foam. IR (Nujol) ν max 1720, 1800 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10].C(=O)(O)[O-].[Na+].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)(Cl)Cl>[Br:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:26]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (2-amino-5-bromophenyl)(2-fluorophenyl)methanone (15 g, 51.0 mmol) and sodium bicarbonate (12.85 g, 153 mmol) in CHCl3 (150 mL) was cooled in an ice bath to 0° C. A solution of 2-bromoacetyl bromide (4.89 mL, 56.1 mmol) was added drop-wise slowly and washed in with CHCl3 (30 ml). The cooling was removed and the mixture was stirred for 2 hr.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[C:45]([O:44][C:42]([N:36]1[CH2:41][CH2:40][N:39]([C:30]([N:12]2[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:33][CH2:34][CH3:35])=[O:31])[CH2:38][CH2:37]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and tert-butyl piperazine-1-carboxylate in an analogous manner as described in example 25. LR-MS: 679.4 [(M+H)+]
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[N:4]([CH3:5])[C:23](=[O:24])[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(=O)Cc1ccccc1
Yield: 60.3 %

Procedure:
To a mixture of S,N-dimethyl-N'-nitroisothiourea (0.5 g), CH3CN (20 ml) and potassium carbonate (0.93 g) was added a solution of phenylacetyl chloride (1.04 g) in CH3CN (2 ml) dropwise at room temperature over 10 minutes under stirring. After stirring for 3 hours, insolubles were filtered off and the filtrate was concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexaneacetone (2:1) to afford 0.54 g of S,N-dimethyl-N'-nitro-N-phenylacetylisothiourea as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH2:26][CH2:27][OH:28])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:28][CH2:27][CH2:26][C:22]1[N:21]([CH2:20][C:18]2[N:19]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[O:16][CH:17]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OCCc1nccn1Cc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCc1nccn1Cc1coc(-c2ccc(O)cc2)n1

Procedure:
A solution of 0.90 g (2.39 mmol) 2-{1-[2-(4-benzyloxy-phenyl)-oxazol-4-ylmethyl]-1H-imidazol-2-yl}-ethanol in 60 ml THF was hydrogenated for 2 hours over 250 mg 10% Pd/C at ambient temperature and pressure. After filtration, the solvent was evaporated to leave 0.55 g (80%) 4-{4-[2-(2-hydroxy-ethyl)-imidazol-1-ylmethyl]-oxazol-2-yl}-phenyl as light yellow crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(CCl)C(=O)O
Reactant: Sc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CSc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Sodium hydride powder (0.86 g, 35.8 mmol) was added to a mixture of 4-(4-chlorophenoxy)thiophenol (3.55 g, 15 mmol) in N,N-dimethylformamide (12 mL) at 0° C. The mixture was warmed to room temperature over 5 minutes, stirred for an additional 20 minutes, and solid chloropivalic acid (1.64 g, 12.0 mmol) was added in one portion. This mixture was heated to 80° C. for 18 hours, cooled to room temperature, and water (1 mL) added. The residue was partitioned between methylene chloride (50 mL) and 2N hydrochloric acid (25 mL). The aqueous layer was separated and washed with additional methylene chloride (2×25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 5% methanol/methylene chloride, gave slightly impure 3-[4-(4-chlorophenoxy)phenylthio]-2,2-dimethyl propionic acid (4 g, 99%). This material was recrystallized from the minimum amount of diethyl ether/hexanes to afford analytically pure acid as a white solid (3.20 g, 80%). mp 84.4-84.9° C.; IR (KBr) 3433 (br), 1732 cm-1 ; 1HNMR (DMSO-d6) δ 1.19 (s, 6H), 3.14 (s, 2H), 6.97 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.9, 2H), 7.40 (d, J=8.8 Hz, 2H), 12.36 (br s, 1H). EIMS(M+): 378. Anal. Calcd. for C17H17SO3Cl: C, 60.62; H, 5.09. Found: C, 60.31; H, 4.96.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:5]=1[CH2:6][OH:7].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18].CC(=O)OCC>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[C:9]([F:13])[CH:10]=[C:11]([F:12])[C:4]=2[F:3])[C:16]=1[C:17]#[N:18]
Reactant: OCc1cc(F)cc(F)c1F
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cc(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a cold (ice water) suspension of sodium hydride (407 mg; 10 mmol) in anhydrous DMF (4 is added a solution of 2,3,5-trifluorobenzyl alcohol (1.62 g; 10 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.56 gm; 11 mmol) in anhydrous DMF (5 mL), and allowed to room temperature over 3 hours. TLC (25% EA/Hex) was incomplete so the reaction was continued at room temperature for an additional 2 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 4.5 hours to give 2.05 grams of 2-fluoro-6-(2,3,5-trifluorobenzyloxy)-benzonitrile.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([F:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])=[N:16][C:12]=2[CH:11]=[CH:10][N:9]=1)(C)(C)C>Cl>[NH2:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([F:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])=[N:16][C:12]=2[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2nc(-c3c(F)cc(C#N)cc3Cl)sc12
Agent: Cl
Product: N#Cc1cc(F)c(-c2nc3ccnc(N)c3s2)c(Cl)c1
Temperature: 50 °C
Yield: 77.9 %

Procedure:
A mixture of [2-(2-chloro-4-cyano-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl]-carbamic acid tert-butyl ester (0.320 mmol) in HCl (4N in dioxane, 2.5 mL) was heated at 50° C. for 3 hours in a sealed vial. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (76 mg, 78% yield over two steps). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J=5.8 Hz, 1H), 7.69 (t, J=1.4 Hz, 1H), 7.53-7.46 (m, 2H), 4.84 (s, 2H).
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:12][C:11]=2[CH:21]=1>FC(F)(F)C(O)=O>[OH:6][C:7]1[C:8]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][C:10]2[O:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:12][C:11]=2[CH:21]=1
Reactant: CC(C)(C)O
Reactant: CCOC(=O)C1=COc2ccc(O)cc2O1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=COc2cc(C(C)(C)C)c(O)cc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
Add 0.425 cm3 (4.5 mmol) of tert-butanol to a solution of 0.5 g (2.25 mmol) of ethyl 7-hydroxy-1,4-benzodioxin-2-carboxylate in 3 cm3 of trifluoroacetic acid. The whole is stirred for 24 hours at room temperature and, after concentrating to dryness under reduced pressure, the crude product is then purified by chromatography on a silica column (eluant:petroleum ether/diethyl ether 80:20). Ethyl 7-hydroxy-6-tert-butyl-1,4-benzodioxin-2-carboxylate is obtained in a yield of 78%.