Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:24][C:23](=O)[NH:22][N:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.O(C1C=CC=CC=1)C1C=CC=CC=1.[NH:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:50][CH2:49]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:24][C:23]([N:48]3[CH2:49][CH2:50][CH:51]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])[CH2:52][CH2:53]3)=[N:22][N:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4nnc(N5CCC(NC(=O)OC(C)(C)C)CC5)o4)c3c2)n1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a stirred solution of 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (0.25 g, 0.74 mmol) in anhydrous DMF (2.5 mL) was added DIPEA (0.25 mL, 1.48 mmol), Ph2O (125 mg, 0.74 mmol) and tert-butyl piperidin-4-ylcarbamate (0.295 g, 1.4 mmol) sequentially. The reaction was stirred for 5 min, BOP (360 mg, 0.8 mmol) was added and the reaction was further stirred for 12 h at RT. The mixture was diluted with water (25 mL) and the resulting suspension was filtered. The solid was triturated with 50% EtOAc in petroleum ether to give tert-butyl (1-(5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)carbamate (80 mg, 21%) as a solid. MS (ESI, pos. ion) m/z: 520.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm: 12.01 (s, 1H), 8.74 (s, 2H), 8.13 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.00 (d, J=7.2 Hz, 1H), 5.40-5.46 (m, 1H), 3.73-3.87 (m, 2H), 3.50 (s, 1H), 3.16 (t, J=10.6 Hz, 1H), 2.98 (t, J=9.2 Hz 1H), 1.84 (s, 2H), 1.33 (s, 17H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>CN1C(=O)N(C)CCC1>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][C:3]4[NH:1][C:2]5[C:15]6[C:14]([C:13]7[C:8]([C:7](=[O:17])[C:6]=6[CH:5]=[CH:4][C:3]=5[NH:1][C:2]=4[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[CH:9][CH:10]=[CH:11][CH:12]=7)=[O:16])=[O:17]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: CN1CCCN(C)C1=O
Product: O=c1c2ccccc2c(=O)c2c1ccc1[nH]c3c(ccc4c(=O)c5ccccc5c(=O)c43)[nH]c12

Procedure:
102.6 g of 1-aminoanthraquinone (97.5% pure) were condensed in the presence of 200 g (190 ml) of N,N'-dimethylpropyleneurea as described in Example 1 to form indanthrone (I).
Reaction SMILES: C(Cl)Cl.[S:4]([NH:14][C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl.[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(N(CC)CC)C>[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:22](=[O:24])[C@H:15]([CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[NH:14][S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of desiccated methylene chloride were added 10 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidine (47) and 6.50 g of L-proline benzyl ester hydrochloride and the mixture was cooled in an ice bath. After adding thereto 2.72 g of triethylamine, 6.05 g of DCC was further added to the mixture and the resultant mixture was stirred for 30 minutes in an ice-bath and stirred overnight at room temperature. Insoluble matters were filtered off and the filtrate was concentrated. The residue thus formed was purified by silica gel column chromatography. By eluting the product with ethyl acetate-benzene (1:1), 13.5 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidyl-L-proline benzyl ester (49) was obtained.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[C:11]([CH:22]=1)=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[O:13][N:14]=2.[I:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=1.O>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[O:13][N:14]=[C:10]3[CH:9]=[CH:8][C:7]([C:28]([C:27]4[CH:34]=[CH:35][C:24]([I:23])=[CH:25][CH:26]=4)=[O:29])=[CH:22][C:11]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(I)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
BuLi 1.6M (0.106 mol) was added dropwise at −70° C. to a solution of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.0816 mol), obtained in Example A1a, in THF (250 ml) under N2 flow. The mixture was stirred at −70° C. for 15 min. A solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.098 mol) in THF (150 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour then brought to room temperature. The mixture was hydrolysed with water, extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (48 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 16.5 g (44%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-iodophenyl)-methanone, mp.196° C. (intermediate 35).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[S:13][C:12]2[N:11]3[CH2:14][C:15]([CH2:18]Cl)(O)[N:16]=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:5]=1>>[Cl:3][C:4]1[S:13][C:12]2[N:11]3[CH2:14][CH:15]([CH2:18][OH:1])[N:16]=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:5]=1
Reactant: [OH-]
Reactant: OC1(CCl)CN2C(=N1)CN=C(c1ccccc1F)c1cc(Cl)sc12
Agent: [Na+]
Product: OCC1CN2C(=N1)CN=C(c1ccccc1F)c1cc(Cl)sc12
Reaction time: 21 h

Procedure:
37.2 g of 2.5N sodium hydroxide solution were added at 60° C. to a suspension of the reaction mixture (RS)-2-chloro-8-chloromethyl-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepin-8-ol obtained in accordance with paragraph e) and stirred under argon for 21 h., subsequently two 18.7 g portions of 2.5N sodium hydroxide solution were added at intervals of two hours and the mixture was stirred for 2 h. The suspension was extracted with sodium chloride solution saturated with dichloro methane in the presence of a small amount of methanol. The dichloromethane extracts were dried with sodium sulphate, filtered and evaporated to dryness in a vacuum. After crystallization of the residue from 5% methanol in dichloromethane 3.3 g of the starting product of step e) were recovered. The mother liquors were evaporated to dryness in a vacuum and the residue was chromatographed on 800 g of silica gel. With 5% methanol in dichloromethane there were eluted 1.5 g of 2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6 6H-imidazo[1,2-a]thieno-[3,2-f][1,4]diazepine-8-methanol which was used without further purification as the starting product for the step described below.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].O[C:14]1[C:15]([O:56][CH3:57])=[CH:16][C:17]2[C:21](CC3C=CC(O[C@@H]4CCCC[C@H]4N4CCCC4)=CC=3)=[C:20]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[CH:43][CH:42]=3)[S:19][C:18]=2[CH:55]=1.[CH3:58][O:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[CH2:69][N:70]1[CH2:74][CH2:73][CH2:72][CH2:71]1)[C:63](O)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[CH3:57][O:56][C:15]1[CH:14]=[CH:55][C:18]2[S:19][C:20]([C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH2:49][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[CH:45][CH:46]=3)=[C:21]([CH2:63][C:62]3[CH:66]=[CH:67][C:68]([CH2:69][N:70]4[CH2:74][CH2:73][CH2:72][CH2:71]4)=[C:60]([O:59][CH3:58])[CH:61]=3)[C:17]=2[CH:16]=1
Reactant: COc1cc2c(Cc3ccc(O[C@@H]4CCCC[C@H]4N4CCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2cc1O
Reactant: COc1cc(C(=O)O)ccc1CN1CCCC1
Agent: O=C(O)C(=O)O
Product: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)c(Cc3ccc(CN4CCCC4)c(OC)c3)c2c1
Yield: 37 %

Procedure:
The free base of the title compound was prepared in 37% yield by essentially following the procedures outlined in Example 41; Part C from 5-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 71, Part C) and 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoic acid (Example 41, Part B). The title compound was prepared by essentially following the procedures outlined in Example 21, Part C from the free base.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=2)=[CH:12][CH:11]=1)[OH:9]>[O-2].[O-2].[Mn+4].ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=2)=[CH:14][CH:15]=1)=[O:9]
Reactant: Cc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2-{4-[1-(2-Methylphenyl)-1-hydroxymethyl]phenyl}-4,4-dimethyl-2-oxazoline (3.0 g), manganese dioxide (20 g) and dichloromethane (50 ml) are mixed at room temperature. The mixture is stirred at room temperature for two hours, and refluxed for three hours. The insoluble materials are removed by filtration through celite, and washed with chloroform, and the mother liquor is concentrated to give 2-[4-(2-methylbenzoyl)phenyl]-4,4-dimethyl-2-oxazoline (2.86 g) as pale yellow oil. 1H-NMR (200 MHz, CDCl3) δ ppm: 1.40 (6H, s), 2.33 (3H, s), 4.14 (2H, s), 7.12-7.54 (4H, m), 7.76-7.92 (2H, m), 7.95-8.14 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>C1COCC1>[CH2:3]([O:4][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14])[CH:2]([CH3:5])[CH3:1]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
To a solution of 2-methylpropan-1-ol (9.6 mL, 0.104 mol) in anhydrous THF (200 mL) was added NaH (60% in mineral oil, 4.565 g, 0.114 mol) in small portions at 0° C. under N2. After it was stirred at room temperature for 30 min, the reaction mixture was cooled down to −70° C. and 2,6-dinitrobenzonitrile (20.0 g, 0.104 mol) was added portionwise. After the addition was complete, the reaction mixture was stirred at −70° C.-RT overnight, then poured into ice water (600 mL). The resultant precipitate was collected by filtration and rinsed with water, hexane, and air dried to provide 2-isobutoxy-6-nitrobenzonitrile as a light yellow solid (34.3 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 1.0 (d, J=6.8 Hz, 6H), 2.04-2.11 (m, 1H), 4.02 (d, J=6.8 Hz, 2H), 7.69-7.71 (m, 1H), 7.84-7.90 (m, 2H). MS 221 (MH+).
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>[H][H].[Pd]>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(F)cc2)CC1

Procedure:
To a methanol (10 mL) solution of 4-(4-fluorophenyl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (100 mg) obtained in Example 352, 10% Pd—C (100 mg) was added, and the reaction solution was agitated in hydrogen stream at room temperature for 1 hour. Suction filtration of the reaction solution was carried out using celite after the reaction ended, and the filtrate was concentrated under reduced pressure. The obtained crude product of 4-(4-fluorophenyl)azepane-1-carboxylic acid tert-butyl ester was used for the next reaction, without further purifying.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].Cl.CCN(C(C)C)C(C)C.[CH3:34][N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C(Cl)=O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[N:35]([CH3:34])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1)c1ccccc1
Reaction time: 3 h
Yield: 119.1 %

Procedure:
(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 400 mg, 1.20 mmol) was treated with 10 mL 4N HCl in dioxane for 2 hours. The mixture was concentrated in vacuo to dryness. It was dissolved in 3 mL DMF/15 mL dioxane. To it were added DIEA (2.09 mL, 12 mmol) and then N-methyl-N-phenylcarbamoyl chloride (610 mg, 3.6 mmol). The mixture was stirred for 3 hours, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated and subjected to flash column with 0 to 4% MeOH in DCM to isolate (R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (513, 530 mg) in quantitative yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[ClH:28].[OH2:29]>C(OCC)C.C(O)(C)C.C(O)C>[OH2:10].[OH2:29].[ClH:28].[ClH:28].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:7]=3[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(Cc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)CC1

Procedure:
A stirred mixture of 5 g. (0.015 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran and 7.5 g. (0.075 mole) of N-methylpiperazine in 15 ml. of ethanol is heated at 45° C. for 1 hour. The reaction mixture is evaporated to provide a residue which is extracted with diethyl ether. The ether extracts are washed with water and with a saturated sodium chloride solution and dried. Evaporation of the ether solution provides a yellow oil which is dissolved in diethyl ether and treated while stirring with a solution of 4N hydrochloric acid in isopropanol until the reaction is complete. The solid is stirred in hot ethanol while adding water until it is all in solution. Cooling provides a fluffy yellow product, 1-methyl-4-(2-nitro-3-phenyl-5-benzofuranylmethyl)piperazine dihydrochloride dihydrate, m.p. 269°-276° C. (dec.), having the structure ##STR8##
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH3:16])=[CH:6][C:5]=1[CH3:17].N.CCOCC>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([I:1])=[C:13]([CH3:15])[N:12]=[C:11]2[CH3:16])=[CH:6][C:5]=1[CH3:17]
Reactant: II
Reactant: Cc1cn(-c2ccc(N)c(C)c2)c(C)n1
Agent: [Ag+2]
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1cc(-n2c(C)nc(C)c2I)ccc1N
Temperature: 55 °C
Yield: 78.1 %

Procedure:
Silver sulphate (21.8 g) and crushed iodine (35.5 g) were added portionwise to a stirred solution of 1-(4-amino-3-methylphenyl)-2,4-dimethylimidazole (25.4 g) in sulphuric acid (100 cm3) cooled to -10°. After heating at 55° C. for 2 hours, the cooled mixture was poured onto ice (500 g). The mixture was cautiously adjusted to pH8 by addition of concentrated ammonia solution (S.G. 0.880) and extracted with chloroform (2×500 cm3). The organic extracts were combined, filtered through "Arbocel" (silica) [Trade Mark], and washed with saturated sodium thiosulphate solution (200 cm3). The organic solution was dried (MgSO4) and evaporated in vacuo to give a residue which, on trituration with ether, gave the title compound (32.25 g) as a crude solid which was used without further purification in Preparation 22.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].C(OCC)(=O)C>C(O)C.CCCCCC>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)CCc1ccc(C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: O=C(O)CCc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
1N NaOH solution was added to a stirred solution of ethyl 3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate (I-85b: 4.8 g, 17.8 mmol) in ethanol and the resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (2% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure, quenched with ice, acidified with 1N HCl and extracted with DCM (2×150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the product 4.2 g (97.6%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]([CH3:24])[CH3:23])[CH:5]=1.[OH-].[Na+]>CO>[CH:22]([C:18]1[N:17]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=3)[CH:7]=2)[C:3]([OH:25])=[O:2])[CH:21]=[CH:20][N:19]=1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2ccnc2C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3ccnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(2-Isopropyl-imidazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (270 mg, 0.81 mmol was dissolved in 10 mL MeOH, and 3N aqueous NaOH (1 mL) was added. The reaction mixture was stirred at room temperature for three hours, then concentrated under reduced pressure. The residue was acidified to pH 3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 234 mg of 3-(2-isopropyl-imidazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]P(OCC)(OCC)=O.C1OCCOCCOCCOCCOC1.[C:37]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C1COCC1.O>[C:40]([O:39][C:37]([N:44]1[CH2:49][CH2:48][C:47](=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([O:4][CH3:3])=[O:21])[CH2:46][CH2:45]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Sodium hydride (526 mg; 12.05 mmol; 1.2 eq.) was added to a cold (0° C.) solution of 2-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (3.45 g; 12.05 mmol; 1.2 eq.) and 15-crown-5 (60 μL; 0.30 mmol; 0.03 eq.) in THF (10 mL) and the reaction mixture was stirred at room temperature for 30 min whereupon a solution of 1-boc-piperidin-4-one (2 g; 10.04 mmol; 1 eq.) in THF (10 mL) was added dropwise over 10 min at 0° C. The reaction mixture was stirred at room temperature for 2 days then diluted with water and extracted with EA (2×). The combined organic phase was washed with 1M (NaOH) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA, 95/5 to 50/50) afforded the title compound (450 mg, 14%) as a white solid. UPLC/MS: (MS+) 332.3 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]12)=[O:4].[OH-].[Na+]>CO>[C:26]([O:25][C:23]([N:22]1[CH:6]2[CH:7]([N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:9][CH:5]2[C:3]([OH:4])=[O:2])[CH2:20][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
A solution of 14 (923 mg, 2.28 mmol) in MeOH (20 mL) was treated with 1M NaOH (7.8 mL) at ambient temperature. After 1.5 h, the solution was concentrated and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 36 as a yellow-colored foam (900 mg) which was used without further purification. Mass spectrum, m/z [391.4] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:31])=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH:31][C:12](=[O:14])[CH2:11][C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)=[CH:18][CH:17]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Product: COc1cc(CC(=O)Nc2nn3cccnc3c2-c2ccc(Cl)cc2)cc(OC)c1
Yield: 8 %

Procedure:
3,5-Dimethoxyphenylacetic acid and the product from Example 99A were processed using the method analogous to that described in example 98 to afford 9 mg (8%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.36-10.57 (bs, 1H), 9.10 (dd, J=6.9, 1.7 Hz, 1H), 8.62 (dd, J=4.1, 1.7 Hz, 1H), 7.66-7.70 (m, 2H), 7.29-7.32 (m, 2H), 7.14 (dd, J=6.9, 4.1 Hz, 1H), 6.47-6.56 (bs, 2H), 6.44 (s, 1H), 3.73 (s, 6H), 3.58 (s, 2H); MS (ESI) m/z 423 (M+H)+.