Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:28])[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[C@H:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:28])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:22][CH:21]=3)=[O:27])[C@H:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Br)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(-c4ccccc4)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 100 °C
Reaction time: 14 h
Yield: 70.3 %

Procedure:
To a mixture of the compound obtained in Example 18 (0.20 g) in toluene (10 mL) and water (0.5 mL) were added phenylboronic acid (0.083 g), tetrakis(triphenylphosphine)palladium(0) (0.039 g) and potassium carbonate (0.047 g), and the mixture was stirred under an argon atmosphere at 100° C. for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.14 g, 69%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:28].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:28])[C:16]=2[N:15]=[C:14]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
0.124 g (0.335 mmol) of 1-[4-(tert-Butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5-oxide was dissolved in 3 ml of methylene chloride. Two ml of concentrated aqueous ammonia (29%) and a solution of 70 mg (0.368 mg) of p-toluenesulfonyl chloride in 1 ml of methylene chloride were added thereto under ice-cooling and the mixture was stirred for 30 minutes, then stirred at room temperature for 3 hours. After brine was added, the reaction mixture was extracted with chloroform and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1 to 20:1 (v/v)) to obtain 0.114 g (0.309 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine shown below as a pale brown solid. ##STR60## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3460, 3370, 3100, 1710, 1640, 1540, 1380, 1260, 1170, 750.
Reaction SMILES: CC([N:5]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][C@@H:28]([C:30]([NH:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:31])[CH2:27][CH2:26][C@H:25]4[CH3:39])[N:21]=[C:20]([NH:40][CH3:41])[N:19]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)C(=O)[O-])(C)C.C([O-])(O)=O.[Na+]>CO.Cl.O>[NH2:5][C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[N:19]=[C:20]([NH:40][CH3:41])[N:21]=[C:22]([N:24]4[C@H:25]([CH3:39])[CH2:26][CH2:27][C@H:28]([C:30]([NH:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[O:31])[CH2:29]4)[CH:23]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: CNc1nc(-c2ccc3c(N(C(=O)[O-])C(C)(C)C)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Temperature: 50 °C
Yield: 51 %

Procedure:
A mixture of 1,1-dimethylethyl[6-(2-(methylamino)-6-{(2R,5S)-2-methyl-5-[(phenylamino)carbonyl]-1-piperidinyl}-4-pyrimidinyl)-1H-indazol-3-yl]carbamate (530 mg, 0.95 mmol) in CH3OH (15 mL) and conc. HCl (0.5 mL) was heated at 50° C. for a total of 6 hours. The residue was taken up in 5 mL of water, to which was added 5 mL of sat. NaHCO3. The resulting suspension was sonicated, and filtered. The yellow solids collected underwent purification by silica gel column chromatography using elution of gradient 1% A in CHCl3 to 60% A in CHCl3 (A was 200/800/20 CH3OH/CHCl3/NH4OH). Trituration of the residue obtained from the chromatography in MTBE (6 mL), followed by drying under vacuum at 50° C. for 20 hours afforded the title compound (221 mg) as a yellow solid. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.33 (d, J=6.8 Hz, 3H), 1.82-1.97 (m, 3H), 2.06-2.16 (m, 1H), 2.57-2.65 (m, 1H), 2.98 (s, 3H), 3.15-3.25 (m, 1H), 6.51 (s, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.34 (t, J=8.1 Hz, 2H), 7.54 (dd, J=8.5, 1.1 Hz, 1H), 7.60 (dd, J=8.6, 1.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.87 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1ccncc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1ccncc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 29.4 %

Procedure:
To a solution of 2.95 g of 1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 2.66 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.2 g of 4-bromo-1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](OCC)=[O:9])[C:3]1=[O:13].[OH-].[NH4+:15]>C(#N)C>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:15])=[O:9])[C:3]1=[O:13]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.50 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate are treated with 11.5 ml of approximately 25% ammonium hydroxide solution, whereupon the mixture is stirred at room temperature for 1 hour. The mixture is treated with acetonitrile and evaporated. The residue is treated five times with acetonitrile and in each case again evaporated. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 163°-164° after recrystallization from methanol/diethyl ether (1:2).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH:14]=2)=[C:5]([CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH:4]=1>CO.[Pd]>[ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]2)=[C:5]([CH:18]2[CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([CH3:24])([CH3:25])[CH2:23]2)[CH:4]=1
Reactant: CCCN1CC=C(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine hydrochloride (50 mg, 0.13 mmol) produced in Example (104g) in methanol (10 mL) was added 10% palladium on carbon (50 mg, wet), followed by stirring for 2 hours at atmospheric pressure and room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure. Hexane was added to the residue to produce a solid, which was then triturated by sonication. The solid was filtered and dried under reduced pressure to give 16 mg of the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:9])[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)ccc1C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-2-methylphenol (1.00 g, 7.93 mmol) and ethylbromoacetate (1.59 g, 9.51 mmol) in DMF (15 mL) was added K2CO3 (1.10 g, 7.93 mmol). After 30 min at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid (30 mL) and water (30 mL), extracted in DCM (3×20 mL), dried over Na2SO4, filtered, concentrated, and dried in vacuo. Desired product obtained as yellow oil (1.30 g, 77%). 1H NMR (CD3OD/400 MHz) δ 7.09 (t, 1H, J=8.8 Hz), 6.58 (m, 1H), 6.56 (m, 1H), 4.71 (s, 2H), 4.23 (q, 2H, J=7.2 Hz), 2.18 (s, 3H), 1.27 (t, 3H, J=7.2 Hz). ES HRMS m/z 212.0847 (M+H calculated for C11H13FO3 requires 212.0849). Step 2: Preparation of ethyl [2-(bromomethyl)-5-fluorophenoxy]acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1.Cl>CN(C=O)C>[CH3:27][C:19]1[CH:18]=[C:17]([CH2:16][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2ccc3cc(C(=O)O)ccc32)c2c(n1)CC=CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
Indole 5-carboxylic acid (0.5 g, 3.1 mmol) was added to a suspension of sodium hydride (0.27 g, 6.8 mmol, 60% oil dispersion) (washed with hexanes) in DMF (20 ml) cooled to 0° C. The reaction was allowed to stir for 1 h and the 4-chloromethyl-2methyl-quinoline (0.72 g, 3.8 mmol) was added. The reaction was allowed to warm to room temperature and stir overnight. The reaction was neutralized with 1 N HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic acid (0.68 g, 69%) as a brown residue, MS (M+H)+=317.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:10]1([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:24]=[CH:23][C:6]=3[N:7]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(CO)cc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
The tert-butyl 4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (1.0 g) was dissolved in a mixture of TFA (2 mL) and DCM (20 mL) and stirred at room temperature. After four hours, the resulting mixture was concentrated to yield (2-(piperazin-1-yl)benzo[d]thiazol-6-yl)methanol as a yellow oil (0.7 g). MS: 250.3 (M+H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCOc1cc(N)ncc1C#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Phenyl chloroformate (4.93 ml, 39.3 mmol) was added drop wise to a mixture of 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20, 3.45 g, 17.86 mmol) and pyridine (6.35 ml, 79 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 5 h at room temperature and then partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with EtOAc and the product obtained by filtration as a white solid. (UPLC-MS 7) tR 0.97; ESI-MS 314.3 [M+H]+.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(C1C=C(C2C=CC=C(N)C=2)C=CC=1)=O)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)c1cccc(-c2cccc(N)c2)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that 3′-amino-biphenyl-3-carboxylic acid ethyl ester (prepared in two steps from 3-nitrophenylboronic acid) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.40 (1H, s), 8.29 (1H, t), 8.12-8.08 (1H, m), 7.85-7.81 (1H, m), 7.64-7.61 (1H, m), 7.57-7.47 (4H, m), 7.41-7.27 (3H, m), 7.06 (1H, d), 4.80 (1H, d), 4.65 (1H, d), 4.39 (1H, d), 4.25 (1H, d), 2.84-2.77 (1H, m), 2.02-1.70 (6H, m), 1.44-1.16 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 61.19; H, 7.07; N, 8.48%; C35H38N4O5.C7H17NO5.1.9H2O requires: C, 61.21; H, 7.19; N, 8.50%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[O:18])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1sc(CCc2ccc(/C=C/CO)cc2)nc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1sc(CCc2ccc(C=CC=O)cc2)nc1-c1ccccc1

Procedure:
(E)-3-[4-[2-(5-Methyl-4-phenyl-2-thiazolyl)ethyl]phenyl]-2-propenol was oxidized with activated manganese dioxide in the same manner as in Reference Example 25 to yield 4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]cinnamaldehyde, which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 94°-95° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13]C)=O)[CH2:6]1)(=[O:3])[CH3:2].[NH3:15]>>[C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([NH2:15])=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CCC[C@@H](NC(C)=O)C1
Reactant: N
Product: CC(=O)N[C@@H]1CCC[C@H](C(N)=O)C1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of cis-methyl 3-acetamidocyclohexanecarboxylate (350 mg, 1.75 mmol) and methanolic ammonia (20 ml) was stirred for 72 h at 90° C. in a steel bomb. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product which was washed with n-pentane to afford 200 mg (57.1%) of cis-3-acetamidocyclohexanecarboxamide as white color solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].OC1C=CC([C:19]([OH:21])=[O:20])=CC=1.[OH-].[Na+]>>[OH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([C:19]([OH:21])=[O:20])=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O

Procedure:
The process for the preparation of highly pure 2,6-diisopropyl phenol (Formula I), comprises reacting p-hydroxy benzoic acid (Formula II) with an alkylating agent in presence of aq. mineral acid at a temperature in the range of 60-65° C. followed by basification with sodium hydroxide to yield crude 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III) including ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V, dimer impurity, 4,4′-oxydibenzoic acid of Formula IV, and the monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI and subsequently (a) washing with toluene at basic pH to remove the ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V; (b) washing with hot water to remove dimer impurity 4,4′-oxydibenzoic acid of Formula IV; (c) washing with methanol-water mixture, to remove monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI, followed by decarboxylation of 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III), free from impurities of Formula IV, V and VI, in presence of high boiling solvent and a catalyst at high temperature to yield 2,6-diisopropyl phenol having purity of 99.9% by HPLC. 2,6-diisopropyl phenol thus obtained is substantially free of ether impurity 1,3-di(propan-2-yl)-2-(propan-2-yloxy)benzene of Formula VII and monoalkylated phenol impurity 2-(propan-2-yl) phenol of Formula VIII.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]=NC2C=CC=CC=2)[C:5]([F:16])=[CH:4][C:3]=1[OH:17]>C(O)C.[Pd]>[NH2:8][C:6]1[C:5]([F:16])=[CH:4][C:3]([OH:17])=[C:2]([F:1])[CH:7]=1
Reactant: Oc1cc(F)c(N=Nc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
42 g (0.18 mol) of 2,5-difluoro-4-(phenyidiazenyl)phenol from Example 5 and 1 g of Pd/C (10%) were initially charged in 650 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 18 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate distilled under reduced pressure, and dried under high vacuum at 70° C. for 4 hours. The residue (24 g) was recrystallized from ethanol and dried. 15 g (60%) of 4-amino-2,5-difluorophenol are obtained as orange-brown powder.
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[OH:4].[C:33]1([C:44](O)=[O:45])[CH:34]=[CH:35][CH:36]=[C:37]2[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:44]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=23)=[O:45])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:21]=2)[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-(benzyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)-phenyl)-1-propanol (405 mg, 0.90 mmol) in acetonitrile (30 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (170 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (259 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (407 mg, 73%).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[CH2:38][CH2:39][CH2:40]I>C(C(C)=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:40][CH2:39][CH2:38][C:37]([F:43])([F:42])[C:36]([F:45])([F:44])[F:35]
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: FC(F)(F)C(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
500 mg of 11β-fluoro-3-hydroxy-7α-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-trien-17-one is dissolved in 15 ml of ethylmethylketone, mixed with 1.1 g of potassium carbonate and 1.5 ml of 1,1,1,2,2-pentafluor-5-iodo-pentane and refluxed for 2.5 hours. For working-up, the reaction mixture is cooled to room temperature, stirred into saturated common salt solution, extracted with ethyl acetate, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Preparative column chromatography on silica gel with a methylene chloride-methanol gradient provides 397 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(4,4,5,5,5-pentafluoro-pentyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:7][C:8]([O:10]C)=[O:9])=[N:2]1.[Li+].[OH-]>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[CH2:7][C:8]([OH:10])=[O:9])=[N:2]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 61.6 (0.12 mmol) in 3:1 THF/MeOH (2.8 mL) was added 1N LiOH (0.7 mL). The mixture was stirred for 1 hour at room temperature, quenched with 1N HCl (0.8 mL), and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to afford 61 (47 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 7.28 (d, 1H), 7.20 (d, 2H), 7.09 (d, 1H), 6.95 (d, 2H), 6.07 (d, 1H), 5.19 (s, 2H), 4.56 (t, 1H), 3.36 (dd, 1H), 2.99 (dd, 1H).