Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:19])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)[OH:10])(C)(C)C.Cl>C(#N)C.O>[NH2:7][C@@H:8]([CH3:19])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)[OH:10]
Reactant: CCc1ccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCc1ccc([C@@H](O)[C@H](C)N)cc1
Reaction time: 3.5 h

Procedure:
To a stirred solution of tert-butyl[(1S,2R)-2-(4-ethylphenyl)-2-hydroxy-1-methylethyl]carbamate (450 mg, 1.51 mmol) in acetonitrile (10 ml) was added aq. HCl (6 N, 3 ml), and stirring was continued for 3.5 h. Then the mixture was diluted with water (10 ml), and acetonitrile was removed in vacuo. The mixture was washed with dichloromethane (20 ml). The aqueous layer was then made alkaline (pH≈10) by addition of aq. NaOH (10 N), and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried with Na2SO4, the solvent was removed in vacuo to afford white solid, 280 mg (97%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1.[Br:10][C:11]1[C:12]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[N:13][C:14](Cl)=[N:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:10][C:11]1[C:12]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[N:13][C:14]([NH:2][CH2:3][C:4]2[O:8][N:7]=[C:6]([CH3:9])[CH:5]=2)=[N:15][CH:16]=1
Reactant: Cc1cc(CN)on1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Temperature: 120 °C
Yield: 30.9 %

Procedure:
A mixture of 5-aminomethyl-3-methylisoxazole hydrochloride (890 mg, 6.0 mmol), 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 578 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.0 mmol) in 1-butanol (10 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool to ambient temperature and volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the titled compound (225 mg, 31%). 1H NMR (DMSO): δ 2.15 (s, 3H), 2.2 (s, 3H), 4.5 (m, 2H), 6.1 (br s, 2H), 7.6 (br s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 366.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (5 g) and 2-fluoro-nitrobenzene (2 ml) were dissolved in N,N-dimethylformamide (150 ml) and heated to 60° C. Thereto was added potassium carbonate (8 g) and the mixture was stirred at 100° C. for 18 hr. After cooling, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diisopropyl ether and dried at 60° C. to give ethyl 2-(2-nitroanilino)-benzo[b]thiophene-3-carboxylate (5.7 g).
Reaction SMILES: [Cl-].[O:2]([CH:9]([CH3:13])[C:10]([OH:12])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[O:2]([CH:9]([CH3:13])[C:10]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:27]=[CH:28][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH2:26][CH2:25]1)=[O:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: COc1ccc(CN2CCNCC2)cc1
Agent: [Cl-]
Product: COc1ccc(CN2CCN(C(=O)C(C)Oc3ccccc3)CC2)cc1

Procedure:
By carrying out the preparation as in Example 12 (Stage A), but using the chloride of 2-phenoxypropionic acid and 1-(4-methoxybenzyl)piperazine, the title product is obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](=O)[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8]>C(O)C>[CH:11]1[CH:10]=[CH:9][C:7](=[O:8])/[C:6](=[CH:5]\[NH:3][CH2:2][CH2:1][NH:4]/[CH:5]=[C:6]2\[C:7]([CH:9]=[CH:10][CH:11]=[CH:12]\2)=[O:8])/[CH:12]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O
Yield: 89.4 %

Procedure:
Ethylenediamine (50 mmol, 3.3 mL) was added via a syringe to a stirred solution of salicylaldehyde (100 mmol, 10.5 mL) in ethanol (100 mL). A yellow precipitate formed immediately. The reaction mixture was refluxed for 3 hours and the solvent was then removed in vacuo to leave a yellow crystalline solid which was washed with diethyl ether (ca. 100 mL) to give salen ligand (C0) (12.0 g, 90%). Mp. 126-130° C. 1H NMR 3.96 (4H, s, CH2CH2), 6.87 (2H, t J=8.4 Hz, 2×HAr), 6.97 (2H, t J=8.7 Hz, 2×HAr), 7.2-7.3 (4H, m, 4×HAr), 8.38 (2H, s, 2×CH═N), 13.23 (2H, s, 2×OH).
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:17][CH2:18][CH3:19])[C:7]=2[N:8]=1.O.O.O.O.O.O.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:3]2[N:4]=[CH:5][C:6]3[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:17][CH2:18][CH3:19])[C:7]=3[N:8]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CCCn1cc(C(=O)O)c(=O)c2cnc(SC)nc21
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: CCCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Yield: 88 %

Procedure:
A mixture containing 1.40 g of 5,8-dihydro-2-methylthio-8-n-propyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 2.94 g of piperazine hexahydrate, and 20 ml of dimethylsulfoxide was heated at 100 - 110°C for 1.5 hours. The precipitate was collected, washed with ethanol, and then recrystallized from water to yield 1.40 g of the product, as colorless needles, m.p. 259°- 261°C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Br)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of N-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide (1.80 g, 4.54 mmol) in acetone (50 mL) and water (5 mL) was added potassium carbonate (1.50 g, 10.8 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo, and the residue was washed with water and t-butyl methyl ether to yield the title compound in 78% yield (1.12 g): mp 222-224° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.60 (t, J=6.0 Hz, 1H), 7.33-7.16 (m, 5H), 4.35 (d, J=6.0 Hz, 2H), 3.97 (t, J=7.2 Hz, 2H), 2.59 (t, J=7.8 Hz, 2H), 2.46 (s, 3H), 2.14-1.94 (m, 2H); MS (ES+) m/z 316.4 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.FC1C=C([N+]([O-])=O)C=CC=1OC1C=CN=C2C=C(C3SC=CN=3)SC=12.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([OH:53])[CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51]>>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51])[O:53][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1[N+](=O)[O-]
Yield: 9 %

Procedure:
Starting from compound 214, following the procedure described above for the synthesis of compound 11 (scheme 2, step 3, example 12) but replacing 2-fluoro-4-nitrophenol with 3-methoxy-4-nitrophenol [Hodgson, C., J. Chem. Soc., 1929, 2778], title compound 215 was obtained in 9% yield. MS (m/z) 383.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+].B(O)O.N1C=CC=CC=1C1C=CC=CN=1>ClCCCl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:19]3[CH2:21][CH2:20]3)[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)C1CC1
Reactant: Clc1cc2nc[nH]c2c(OCc2ccccc2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Clc1cc2ncn(C3CC3)c2c(OCc2ccccc2)n1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
In a separate flask 4-(benzyloxy)-6-chloro-3H-imidazo[4,5-c]pyridine 2.24 (502 mg, 1.93 mmol), cyclopropane boronic acid (334 mg, 3.89 mmol) and Na2CO3 (415 mg, 3.9 mmol) were taken up in 1,2-DCE (13 mL). The aforementioned catalyst mixture was then added to this mixture, washing with 4×1 mL 1,2-DCE. The resulting mixture was heated to 70° C. and was stirred open to the air. After 7 h, additional Na2CO3 (215 mg, 2.03 mmol) and boronic acid (170 mg, 2.0 mmol) were added along with a heated suspension of Cu(OAc)2 (182 mg, 1.0 mmol) and 2,2′-bipyridine (155 mg, 0.99 mmol) in 1,2-DCE (3 mL). After an additional 1.5 h, additional boronic acid (340 mg, 4.0 mmol) and Na2CO3 (415 mg, 3.9 mmol) were added and the reaction was capped and stirred overnight. After an additional 14.5 h, additional boronic acid (150 mg, 1.7 mmol) and Na2CO3 (215 mg, 2.03 mmol) were added and the mixture was stirred open to air. After an additional 1.5 h, the reaction mixture was cooled to r.t., was diluted with EtOAc (75 mL), and was filtered through Celite. The filtrate was washed with half-saturated aqueous NH4Cl (75 mL), water (50 mL), and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (0% to 5% THF in DCM) provided 4-(benzyloxy)-6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridine 2.35.
Reaction SMILES: II.ClC1C=CC(/C=[CH:11]/[C:12]2[N:13]=[C:14]3[S:22][CH:21]=[CH:20][N:15]3[C:16](=[O:19])[C:17]=2[I:18])=CC=1>C(#N)C>[I:18][C:17]1[C:16](=[O:19])[N:15]2[C:14]([S:22][C:21]3[CH:16]=[CH:17][CH:12]=[CH:11][C:20]=32)=[N:13][C:12]=1[CH3:11]
Reactant: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Agent: II
Solvent: CC#N
Product: Cc1nc2sc3ccccc3n2c(=O)c1I

Procedure:
A stirred solution of the Step 1 intermediate (9 g, 41.613 mmol) in acetonitrile (150 ml) was reacted with ceric ammonium nitrate (11 g, 20.803 mmol) followed by iodine (6 g, 24.961 mmol) according to the procedure outlined in Intermediate 1, Step 3 to give 9 g of the product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) 1H NMR (300 MHz, DMSO-d6) δ 3.15 (s, 3H), 7.54-7.60 (m, 2H), 8.00-8.07 (m, 1H), 8.84-8.90 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:25]3[CH2:28][N:27]([C:29](=[O:43])[CH2:30][CH2:31][N:32]([CH2:40][CH2:41][OH:42])C(=O)OC(C)(C)C)[CH2:26]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=12>CC(C)=O>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:25]3[CH2:26][N:27]([C:29](=[O:43])[CH2:30][CH2:31][NH:32][CH2:40][CH2:41][OH:42])[CH2:28]3)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[C:4]=12
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C(=O)CCNCCO)C1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 14.3 %

Procedure:
2 mL of an 6 N aqueous solution of hydrochloride were added to the mixture of tert-butyl N-(3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.040 g, 0.000070 mol). in acetone (5 mL). The mixture was stirred at 45° C. for 1.5 hours. The solvent was removed under removed pressure. Water (10 mL) was added to the residue, the mixture was lyophilized. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-[(2-hydroxyethyl)amino]-1-propanone (0.003 g, 0.00001 mol).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1cccc(F)c1
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (61 mg, 78%), MS (ISP) m/z=313.6 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl.O1CCOCC1>>[CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reaction time: 8 h

Procedure:
(R)—N—((R)-Cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.000765 mol), ethanol (2.7 g, 0.059 mol), and 4.0 M of hydrogen chloride in dioxane (2.7 mL, 0.011 mol) were combined and stirred overnight. Reaction was concentrated to down to oil and then redissolved and washed with ethanol for 3 times, and concentrated. The residue was dried on the high vacuum overnight to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([NH:18]C(=O)OC(C)(C)C)[CH:7]=[CH:6][C:5]2=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C:8]1[CH:9]=[C:10]2[C:5]([C:4]3[CH:3]=[C:2]([Br:1])[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]=3[NH:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 6-bromo-8-carbamoyl-9H-carbazol-2-ylcarbamate (2.2 g, 5.44 mmol) was suspended into CH2Cl2 (30 mL). TFA (11 mL, 143 mmol) was added. The mixture was stirred for 1 hr at r.t. The mixture was concentrated to dryness. Saturated NaHCO3 water solution was added and stirred for 30 mins and filtered. The off white solid was collected and washed with water 2× and air-dried overnight to give the titled product. MS (ESI) m/z 303.95 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[NH:12][C:11]([CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[CH3:15])=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH:1]1([CH2:7][C:8]2[NH:12][C:11]([CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)[CH3:15])=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Cc1ncc(CC2CCCCC2)[nH]1)c1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Cc1ncc(CC2CCCCC2)[nH]1)c1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
To a 25 mL one neck round bottom flask was added tert-butyl 4′-{2-[5-(cyclohexylmethyl)-1H-imidazol-2-yl]-1-methylethyl}biphenyl-2-carboxylate (35.7 mg), which was treated with a mixture of TFA/CH2Cl2 (1.5 mL/1.5 mL) at rt for 2 hours. Then the solvent was removed by rotary evaporation and the resulting residue was coevaporated with toluene/H2O three times. The resulting crude product was purified by PrepTLC (2000 uM, 10% MeOH/CH2Cl2) to afford 4′-[2-[5-(cyclohexylmethyl)-1H-imidazol-2-yl]-1-methylethyl]-[1,1′-biphenyl]-2-carboxylic acid. 1HNMR (CD3OD, 500 MHz, ppm): 7.52 (1H, br), 7.38 (2H, br), 7.32 (2H, br), 7.28 (1H, br), 7.10 (2H, br), 6.87 (1H, s), 3.20 (1H, br), 3.08 (1H, br), 2.99 (1H, br), 2.41 (2 h, br), 1.58-1.73 (4H, m), 1.48 (1H, m), 1.32 (3H, br), 1.14-1.22 (4H, m), 0.88 (2H, m); m/z (ES) (M+H)+=403).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:18]([N:26]1[CH2:31][CH2:30][CH2:29][C:28]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)([CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[OH2:2].[ClH:46].[C:18]([N:26]1[CH2:31][CH2:30][CH2:29][C:28]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)([CH2:32][CH2:33][CH2:34][N:9]2[CH2:8][CH2:7][C:6]([O:5][CH2:4][CH2:3][OH:2])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10]2)[CH2:27]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: OCCOC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCCC(CCCN2CCC(OCCO)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A mixture of 1 g of 4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride, 1.7 g of the compound obtained in step B of EXAMPLE 1 and 0.65 g of K2CO3 in 15 ml of DMF is heated at 60° C. for 2 hours and the reaction mixture is then stirred overnight at RT. It is poured into water and extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product, m.p.=120-123° C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][OH:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a rapidly stirring solution of 8.5 g (40 mmol) diphenyl acetic acid in 100 mL dry THF, at room temperature, was added 3.04 g (80 mmol) of LAH. The suspension was stirred at room temperature for 1 hour and then cooled to 0 degrees C. The excess LAH was decomposed by slow addition of 10% NaOH (200 mL aqueous solution). The product was extracted with AcOEt, dried over MgSO4 and concentrated under vacuum to yield 7.1 g (90%) of 2,2-diphenyl ethanol (12).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:4][S:5][CH2:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:25][C:26]([NH:2][C:3]2[CH2:4][S:5][CH2:6][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(=O)C1=C(N)CSC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1=C(NC(=O)NC2CCCCC2)CSC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.3 parts by weight of 3-amino-4-methoxycarbonyl-1,5-dihydrothiophene hydrochloride, 6.0 parts by weight of triethylamine, 7.4 parts by weight of cyclohexyl isocyanate and 30 parts by weight of acetonitrile were combined, and the mixture was stirred for 3 hours at 25° C. and then evaporated down. The residue was washed with water and recrystallized from toluene. 4.5 parts by weight of N-cyclohexyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 153°-154° C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)cc1
Yield: 63.1 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 1-(4-nitrophenyl)ethanone (6 g, 36.36 mmol, 1.00 equiv) in ethanol (100 mL), water (15 mL). This was followed by the addition of NH4Cl (3.85 g, 72.64 mmol, 2.00 equiv) in several batches. To this was added Fe (10.18 g, 181.79 mmol, 5.00 equiv) in several batches, while the temperature was maintained at reflux. The resulting mixture was heated to reflux for 2 h. The solids were filtered out and the resulting filtrate was concentrated under vacuum. The residue was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.1 g (60%) of 1-(4-aminophenyl)ethanone as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]([OH:16])=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1(C)C=CC=CC=1.CCOCC>[CH:1]1[C:13]2[CH:12]([C:14]([NH2:23])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: NC(=O)C1c2ccccc2-c2ccccc21

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 21A, using 9-fluorenecarboxylic acid (6.00 g, 28.5 mmol) and oxalyl chloride (3.5 ml, 39.9 mmol) in 30 ml of toluene to provide a clear oil that was dissolved in Et2O and treated with ammonia.