Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:16]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([C:36]3[NH:40][C:39]([C:41]4[N:46]=[CH:45][C:44]([CH:47]=[O:48])=[CH:43][CH:42]=4)=[CH:38][CH:37]=3)[CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH:28]([C:36]3[NH:40][C:39]([C:41]4[N:46]=[CH:45][C:44]([CH:47]([OH:48])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:43][CH:42]=4)=[CH:38][CH:37]=3)[CH2:29][CH:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)CC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution of dimethylsulfone (446 mg) in tetrahydrofuran (10 mL) was added dropwise lithium hexamethyldisilazide (1.6M tetrahydrofuran solution) (2.7 mL) at −78° C., and the mixture was stirred for 1 hr. To the reaction mixture was added dropwise a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The obtained pale-yellow amorphous solid was subjected to basic silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (270 mg, yield 22%) as a colorless amorphous solid. MS: 559 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.C1COCC1.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc(N2CCN(C(=O)c3ccccc3)CC2)c1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of 3-iodo-nitrobenzene (3.0 g, 12.0 mmol), piperazine (1.6 g, 18.1 mmol), copper (I) iodide (0.23 ml, 1.2 mmol) and potassium carbonate (3.3 g, 24.1 mmol) in 40 ml DMSO was stirred at 45° C. for 16 hours. The run was quenched with 10 ml water and extracted with ethyl acetate (3×30 ml). The extraction was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. 1-(3-Nitrophenyl)piperazine hydrochloride (2.0 g, 80%) was obtained when bubbling the HCl gas in ether solution. A solution of 1-(3-nitrophenyl)piperazine (1.50 g, 7.2 mmol), benzoyl chloride, and triethylamine (5.0 ml, 36.1 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. (4-(3-Nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 73%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). The obtained (4-(3-nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 3.8 mmol) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (0.12 mg, 10%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. (4-(3-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.81 g, 80%) was obtained by flash column chromatograph (90% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCl gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.25 (s, br, 4H), 3.53 (d, br, 4H), 6.83 (dd, J=1.2, 7.7 Hz, 1H), 6.99 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.44-7.48 (m, 5H), 10.35 (s, br, 2H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 42.4, 48.1, 110.0, 112.8, 115.1, 120.2, 127.1, 127.2, 128.4, 129.6, 129.9, 130.2, 135.7, 151.0, 169.1.
Reaction SMILES: [OH:1][C@H:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:22]([O:33][CH:34]([CH3:36])[CH3:35])[CH:21]=2)=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.O1CCOCC1.[ClH:49]>O1CCOCC1>[ClH:49].[OH:1][C@H:2]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:3][NH:4][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:22]([O:33][CH:34]([CH3:36])[CH3:35])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CC(C)Oc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1cc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)ccc1C(=O)NS(C)(=O)=O
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-[3′-(isopropoxy)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate (65 mg) in 1,4-dioxane (2 ml) was added hydrochloric acid 1,4-dioxane solution (4N, 4 ml) at room temperature and the mixture was stirred at the same temperature for 2.5 hours. The mixture was evaporated under reduced pressure to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-isopropoxy-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (38 mg).
Reaction SMILES: FC(F)(F)C(O)=O.COC(=O)CC1CC2C(=CC(OCCCNC(N)=N)=CC=2)NC1=O.C[O:33][C:34](=[O:59])[CH2:35][C:36]1[C:37](=[O:58])[N:38]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[C:41]([O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH:40]=2>>[CH2:51]([N:38]1[C:39]2[C:44](=[CH:43][CH:42]=[C:41]([O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH:40]=2)[CH:45]=[C:36]([CH2:35][C:34]([OH:59])=[O:33])[C:37]1=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: COC(=O)Cc1cc2ccc(OCCCN)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCOc1ccc2cc(CC(=O)O)c(=O)n(Cc3ccccc3)c2c1

Procedure:
The title compound was prepared according to the procedure of Example 84 except that [7-(3-guanidino-propoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester trifluoroacetate was replaced with [1-benzyl-7-(3-aminopropoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:17])[NH:7][C:6](=[O:18])[CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:17])[NH:7][C:6](=[O:18])[C:5]=1[Br:1]
Reactant: BrBr
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(Br)c(=O)[nH]c(=O)n1Cc1ccccc1
Reaction time: 6 h

Procedure:
A solution of bromine (33.17 ml) in acetic acid (300 ml) was added slowly to a solution of 6-amino-1-benzyluracil and anhydrous sodium acetate (93.29 g) in acetic acid (300 ml) and stirred for 6 hours. The reaction mixture was cooled in ice-cold water. The precipitate was filtered and dried under vacuum to provide 6-amino-1-benzyl-5-bromouracil (134.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)=[CH:5][C:4]=1[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][CH2:15][C:4]1[CH:5]=[C:6]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2nnn(C)n2)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nnn(C)n2)cc1CBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg, 0.45 mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined in methylene chloride (3 mL) and cooled to 0° C. N-Bromosuccinimide (170 mg, 0.95 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with methylene chloride and washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) gave 80 mg (63%) of the desired material. LC/MS (HPLC method 3): tR=2.69 min, 285.02 (MH)+.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([Cl:23])=[O:22])=[CH:17][CH:16]=1.CCOCC>C(O)(C(F)(F)F)=O.CC(C)=O>[ClH:23].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])=[O:22])=[CH:17][CH:16]=1
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc(C=CC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 4.5 h
Yield: 70 %

Procedure:
7.12 g (0.036 moles) of carnitine hydrochloride are dissolved in 12 mls of CF3COOH, and to the solution an excess (25 mls) of p-methoxy cinnamoyl chloride is added and the mixture kept under stirring at 40°-50° C. for 4-5 hours. At the end of this period of time the mixture is diluted with 90 mls of acetone and some ether is slowly added till complete precipitation. The mixture is filtered and the precipitate which has the tendency to become hygroscopic is quickly washed with ether and dried under vacuum at a temperature not exceeding 50° C; 9 g of a product are obtained (yield 70%) having the following characteristics:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([NH2:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18]>CN(C=O)C>[NH2:8][C:5]1[N:6]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:7]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: CSc1n[nH]c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(N)n(CC(=O)N2CCN(c3ccc(Cl)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Methylsulfanyl-2H-[1,2,4]triazol-3-ylamine (0.216 g, 1.7 mmol) was taken in dry DMF (15 ml) and dry potassium carbonate (800 mg) and KI (20 mg) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded crude product that was purified by column chromatography (CHCl3/MeOH): 1H NMR (300 MHz, DMSO-d6): δ 7.24 (d, 2H), 6.98 (d, 2H), 6.24 (s, 2H), 4.84 (s, 2H), 3.57 (m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Li+]>C1COCC1.O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(NC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-methylamino-1,3-thiazole-4-carboxylate (300 mg, 1.611 mmol) was dissolved in THF/water mixture and 1M litium hydroxide (3.22 ml, 3.22 mmol) was added. The reaction mixture was stirred at RT for 3 hours, pH was adjusted to acidic and the mixture was evaporated to dryness to yield the title compound. 1H-NMR (400 MHz; DMSO-d6): δ 2.84 (s, 3H), 7.46 (s, 1H), 7.90 (bs, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([Cl:25])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccccc1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)=[O:4].[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[Br:24][C:7]1[N:6]=[C:5]([C:3]([N:2]([CH3:23])[CH3:1])=[O:4])[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:8]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Cc1c(Br)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
N,N,5-Trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.14 g, 0.43 mmol) was dissolved under argon in DMF (2 ml) in a vial. N-Bromosuccinimide (0.089 g, 0.5 mmol) was added. The vial was sealed and stirred for 30 minutes. The crude mixture was purified on preparative HPLC to give 0.100 g (57%) of the title compound as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13](CC4C=CC=CC=4)[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1ccc(CN2CCCC(Cc3ccc4c(c3)OCO4)C2)cc1
Solvent: CO
Product: c1cc2c(cc1CC1CCCNC1)OCO2

Procedure:
1.40 g (4.5 mmol) of (+)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidine is dissolved in 35 ml MeOH and 1 ml AcOH and hydrogenated over Pd/C 10% (0.3 g) for 2 d until hydrogen absorption is complete. The mixture is filtered over Celite®, and the filtrate is evaporated, diluted with CH2Cl2, washed with sat. aq. Na2CO3 solution and evaporated to give (+)-3-benzo[1,3]dioxol-5-ylmethyl-piperidine ([α]Drt=5.90 (c=0.5, DMSO)) which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][CH:22]=3)=[CH:26][CH:27]=2)[C:32]1=[O:36])[CH3:12]
Reactant: Cc1nc(-c2ccc(-n3cc[nH]c3=O)cc2)cs1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: Cc1nc(-c2ccc(-n3ccn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)cs1

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2-methyl-4-thiazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2-methyl-4-thiazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 30).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:31])([F:32])[F:17])[CH:21]=2)[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2cccc(OC(F)(F)F)c2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11]>C(O)(=O)C>[C:1]([NH:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N[C@H](CO)C(=O)O
Temperature: 32.5 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (23.4 ml) was added to the suspension of (R)-2-amino-3-hydroxypropanoic acid compound of formula-3 (20 grams) in acetic acid (300 ml) and stirred for 24 hours at 30-35° C. After completion of the reaction, acetic acid was removed by distillation followed by co-distillation with tetrahydrofuran. Isopropyl alcohol (60 ml) and methyltertiarybutylether (120 ml) was added to the obtained residue and stirred for 30 minutes. The obtained solid was filtered off and then solvent from the filtrate was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of methyl 2-methyl-2′-(trifluoromethyl)biphenyl-4-carboxylate, prepared in step 1 (3 g; 10.19 mmol; 1 eq.) in EtOH (90 mL), was added at RT an aqueous solution of sodium hydroxide (6.12 mL; 5 M; 30.58 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under vacuum to give a brown solid. It was taken up in water (400 mL) and the aqueous phase was washed twice with EtOAc (200 mL). Aqueous phase was acidified with concentrated HCl (2 mL) to pH 2. Then it was concentrated under vacuum until a precipitate was formed (⅓ of volume). The suspension was filtered off and dried under vacuum, affording the title compound as a beige solid (2.41 g, 84%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.03 (s, 1H), 7.91-7.68 (m, 5H), 7.38-7.36 (d, J=8.27 Hz, 1H), 7.27-7.25 (d, J=8.24 Hz, 1H), 2.05 (s, 3H). LC/MS (Method A): 279.0 (M−H)−. HPLC (Method A) Rt 4.49 min (Purity: 95.7%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH3:20][NH2:21]>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:21][CH3:20])=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(Cl)c2ccccc21
Solvent: C1CCOC1
Product: CCCCn1c(=O)c([N+](=O)[O-])c(NC)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
11 g (0.039 mole) of Compound d obtained in Reference Example 4 was dissolved in 100 ml of tetrahydrofuran, and 30 ml (0.39 mole) of 40% methylamine was added with ice cooling, followed by stirring at room temperature for one hour. Then, the solvent was evaporated under reduced pressure, and water was added to the residues. The precipitate was collected by filtration and dried, to afford 9.2 g of Compound w (yield: 87%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH:29]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30]([O:32]C)=[O:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.O>C1COCC1>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH:29]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]([OH:32])=[O:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
In a similar manner as described in step 2 of Example 12, the title compound was prepared from methyl 2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.186 g, 0.355 mmol), prepared in the previous step, and 1N NaOH (0.53 mL, 0.53 mmol) in 2:2:1 THF:MeOH:water (25 mL). The starting material required heating to dissolve in the THF (10 mL). After the solution was clear, MeOH (10 mL) was added followed by the water (5 mL). The reaction was complete after 2.5 hours. The solids were isolated by filtration to give 2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid as a beige solid (0.17 g, 94%), mp 194–196° C. (dec). Elemental Analysis for C35H27NO3.0.23 H2O Calc'd: C, 81.83; H, 5.39; N, 2.73. Found: C, 81.07; H, 5.44; N, 2.56.
Reaction SMILES: BrC1C=CC(C2C=CC(CCC=O)=CN=2)=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]=[CH:34][O:35]C)=[CH:27][N:26]=2)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH:34]=[O:35])=[CH:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: COC=CCCc1ccc(-c2ccc(Br)cc2)nc1
Agent: O=CCCc1ccc(-c2ccc(Br)cc2)nc1
Product: O=CCCCc1ccc(-c2ccc(Br)cc2)nc1

Procedure:
3-[2-(p-Bromophenyl)-5-pyridyl]propionaldehyde is converted in an analogous manner to paragraph (a) into 2-(p-bromophenyl)-5-(4-methoxy-3-butenyl)pyridine and this is then hydrolyzed in an analogous manner to paragraph (b) to give 4-[2-(p-bromophenyl)-5-pyridyl]butyraldehyde.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:28].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]3[C:8](=[O:28])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Product: COc1ccccc1-c1cc(N2CCN(C(C)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 50.3 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 18; 82.0 mg) was reacted with 1-acetylpiperazine (57.7 mg) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (48.2 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)cc(Cl)c3n2CCc2ccc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 6,8-dichloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.