Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:41][C:42]1[N:43]=[CH:44][NH:45][CH:46]=1)[C:21]([NH:23][C@@H:24]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:25]([OH:33])[CH2:26][C@@H:27]([CH:30]([CH3:32])[CH3:31])[CH:28]=[CH2:29])=[O:22].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[CH:35]1([CH2:34][C@H:24]([NH:23][C:21](=[O:22])[C@@H:20]([NH:19][C:9](=[O:11])[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:41][C:42]2[N:43]=[CH:44][NH:45][CH:46]=2)[C@@H:25]([OH:33])[CH2:26][C@@H:27]([CH:30]([CH3:32])[CH3:31])[CH:28]=[CH2:29])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)Cc1ccccc1)C(C)C
Yield: 42.6 %

Procedure:
A mixture of 83 mg (0.345 mmol) of dibenzylacetic acid, 90 mg (0.23 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2 -hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 0.045 ml (0.345 mmol) of 4-ethylmorpholine, 93 mg (0.69 mmol) of HOBT and 85 mg (0.41 mmol) of DCC in 15 ml of dimethylformamide was stirred at room temperature overnight. Thereafter, the separated precipitate was filtered off and the filtrate was evaporated to dryness. The residue was then dissolved in ethyl acetate and the solution was washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed on 30 g of silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia. Crystallization of the residue from methylene chloride/methanol/hexane yielded 60 mg of (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2 -hydroxy-4-isopropyl-5-hexenyl]-α-(2,2-dibenzylacetamido)imidazole-4-propionamide, melting point 98°.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1c(Cl)cccc1CO
Product: Nc1c(Cl)cccc1COCc1ccccc1

Procedure:
This material was prepared from 2-amino-3-chlorobenzyl alcohol and benzyl bromide by the general procedure outlined in Example 82. The product was purified by Kugelrohr distillation to yield an oil, bp 118°-125° C. (0.1 mm). The product was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:26][CH2:27][O:28][CH3:29])[N:15]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[Cl:30]CCl.CO>O1CCOCC1>[ClH:30].[NH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:26][CH2:27][O:28][CH3:29]
Reactant: ClCCl
Reactant: COCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCc1nc2c(N)nc3cccnc3c2n1CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydrochloric acid in dioxane (58 mL of 4 M) was added to a solution of tert-butyl N-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin 1-yl]ethyl}carbamate (3 g) in a small amount of dichloromethane/methanol. The reaction; mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure to provide 3.7 g of crude 1-(2-aminoethyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\Br)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Zn]CC)[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[CH2:24][CH3:25])[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccccc2)COC1(C)C
Product: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1

Procedure:
In analogy to example 162c (S)-4-((Z)-2-bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with diethylzinc to give (S)-2,2-dimethyl-4-((E)-2-phenyl-but-1-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester. Colourless oil. MS (ISP): 332.3 ([M+H]+).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>>[CH3:44][N:45]([CH3:49])[C:46]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:47]
Reactant: CN(C)C(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]3[O:21][N:20]=[C:19]([CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[N:18]=3)=[C:4]2[CH2:3]1.CN>C(O)C>[NH2:23][CH2:22][C:19]1[N:18]=[C:17]([C:16]2[N:15]=[CH:14][N:5]3[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=23)[O:21][N:20]=1
Reactant: CN1Cc2c(-c3nc(CN4C(=O)c5ccccc5C4=O)no3)ncn2-c2ccccc2C1=O
Agent: CN
Solvent: CCO
Product: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccccc2C1=O

Procedure:
13 g (29.5 mmol) of 5,6-dihydro-5-methyl-3-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred with 90 ml of methylamine (33% in ethanol) and 40 ml of ethanol at 80° for 3 hours. The solution was concentrated, the residue was taken up in methylene chloride and 53 ml of 4N hydrochloric acid and the solution was washed three times with methylene chloride. The aqueous phase was made alkaline with 55 ml of 4N sodium hydroxide solution and extracted six times with methylene chloride. After drying the combined organic solutions and evaporating the solvent there were obtained 9 g (100%) of (3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 183°-185°, which was used without further purification as the starting material for the Example described hereinafter.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:31][CH:30]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: NCc1ccc(N2CCOCC2)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(4-morpholin-4-ylphenyl)methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.46-7.40 (m, 3H), 6.94 (d, 2H), 6.81 (d, 2H), 5.47 (t, 1H), 3.95 (d, 2H), 3.87 (t, 4H), 3.72 (t, 2H), 3.15 (t, 4H), 1.88-1.80 (m, 2H), 1.52-1.42 (m, 2H), 0.99 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.2, 151.3, 135.8, 131.8, 129.9, 128.9, 128.8, 127.6, 125.1, 115.9, 108.0, 67.0, 49.4, 48.1, 40.4, 30.5, 20.3, 13.8; Mass Spectrum: M+H+ 456.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Temperature: 80 °C
Yield: 63 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (160 mg, 0.72 mmol), 5-methoxy-3-(piperidin-4-yl)-1H-indole (obtained as described in PCT Int. Appl. WO 2004006922, Intermediate 37) (166 mg, 0.72 mmol) and DIPEA (0.138 mL, 0.79 mmol) in DMF (2 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was cooled to room temperature and quenched in water (10 mL) to give a precipitate. The solid was collected by filtration, washed sequentially with water, acetonitrile and ether, and air dried to give 6-[4-(5-methoxy-1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (189 mg, 63%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1)#[CH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:18])=[N:6][CH:7]=2)[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1ncc(Br)cn1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)cc(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 5-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (573 mg, 3.0 mmol), 1-ethynyl-3,5-dimethoxybenzene (483 mg, 3.0 mmol), triphenylphosphine (157 mg, 0.60 mmol), bis(triphenylphosphine)palladium(II) chloride (210 mg, 0.30 mmol), copper(I) iodide (57 mg, 0.30 mmol) and diethylamine (1.50 ml, 15.0 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen three times, and then stirred at 80° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was cooled to RT, quenched with water (20 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=4:1) to afford the title compound as a yellow solid (460 mg, 39%). MS (ES+) C21H18N4O4 requires: 390. found: 391 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16](OCC)(=[O:18])[CH3:17].O>C1C=CC=CC=1>[C:16]([CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10]1=[O:13])(=[O:18])[CH3:17]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)C1CC(c2ccccc2)CCC1=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 4-phenylcyclohexanone (10 mmol, Lancaster) in benzene (5 ml) is added dropwise to a suspension of NaH (20 mmol) in absolute ethyl acetate (20 mmol) and the reaction mixture is stirred after complete evolution of the gas for 3 h at 40° C. Then it is mixed with water, the reaction mixture is extracted three times with ether, the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and the solvent is removed in a vacuum. After column chromatography purification on silica gel with hexane/EtOAc 15:1 a clean product is obtained. tR 2.14; MS (pos. Ion.) m/z 217.26 [M+H]+. (J. Med. Chem. 1989, 32(2), 351-357).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])=[CH:17][CH:16]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of the product prepared in Step B (1160 mg, 6.0 mmol, 1 eq), 4-chlorophenylboronic acid (2.9 g, 18.0 mmol, 1 eq), Cu(OAc)2 (2.18 g, 12.0 mmol, 2 eq), 4 A molecular sieves (3 g), pyridine (1.94 mL, 4.0 mmol, 4 eq) in DCM (40 mL) was stirred at room temperature for 2 days. The resulting suspension was filtered through CELITE, washed with DCM, and concentrated. The resulting residue was dry packed and purified by flash chromatography (120 g column) eluting with 4 to 8% EtOAc/heptane to yield methyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH2:11]N(C)C)=[C:7]([OH:15])[C:6]1=[S:16])[CH2:2][CH2:3][CH3:4].IC>C(Cl)Cl>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:15])[C:6]1=[S:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc(CN(C)C)c(O)c1=S
Solvent: CI
Solvent: ClCCl
Product: CCCCn1ccc(C)c(O)c1=S
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 1-butyl-3-hydroxy-4(N,N-dimethylaminomethyl)pyridine-2-thione (2-034-05) (1.0 g) in methylene chloride (20 mL) was added iodomethane (2.1 g) at room temperature. After the reaction mixture was stirred for 1 h, the solvent was evaporated under reduced pressure. To the residue were added ethanol (20 mL) and triphenylphosphine (1.6 g), and the reaction mixture was stirred at 75° C. for 20 h, and evaporated under reduced pressure. To the residue were added methanol (10 mL) and 1 mol/L aqueous sodium hydroxide solution (8 mL), and the reaction mixture was stirred at 60° C. for 2 h, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (toluene/acetone=4/1) to give 1-butyl-3-hydroxy-4-methylpyridine-2-thione (2-034-06) (0.57 g, 70%) as an oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]([CH3:27])=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[C:12]=1[CH:13]1[CH2:15][CH2:14]1)=[O:7])C>>[CH:13]1([C:12]2[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)[N:10]=[C:9]([CH3:27])[C:8]=2[C:6]([OH:7])=[O:5])[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1c(C)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(-c2cccc(OC(F)(F)F)c2)c(C2CC2)c1C(=O)O

Procedure:
The title compound was prepared by sodium hydroxide hydrolysis of the minor isomer-5-cyclopropyl-3-methyl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester from formation of intermediate 6. MS: 327.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1.[CH2:20](Br)[CH:21]([CH3:23])[CH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](C(C)C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@@H](C(C)C)N1CC(C)C

Procedure:
(1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:31])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:31][C:21]1[N:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:24][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:32])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccccc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccccc2)sc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {6-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-indol-1-yl}-acetic acid as off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH3:22].I([O-])(=O)(=O)=[O:24].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:22][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=1)=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccccc2S(C)=O)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of 3-methyl-2-(2-methylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.32 g), methanol (4 ml) and water (6 ml), sodium periodate (0.42 g) was added under ice-cooling. The mixture was heated to room temperature, and stirred for 1 hour, and then heated to 40° C., and stirred with heating for further 1 hour. Into the reaction mixture cooled to room temperature saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform 2 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.32 g of 2-(2-methylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 2).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>CCO.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH:2]([C:1]#[N:5])[C:3]#[N:4])=[CH:9][CH:8]=1
Reactant: N#CCC#N
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of malononitrile (3.15 mL, 50.0 mmol) in 50 mL of 95% EtOH, 4-fluorobenzaldehyde (5.28 mL, 50 mmol) was added and the mixture was stirred at room temperature overnight. The white solid precipitated out and this suspension was diluted with 25 mL of EtOH then treated with sodium borohydride (0.946 g, 25.00 mmol) in one portion. This mixture was stirred at ambient temperature for 2 hours until reaction was complete. Water and 1N HCl solution was added carefully to quench sodium borohydride. The precipitate was then filtered, washed with copious amount of water, air-dried to give 5.92 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.43 (m, 2H) 7.06-7.17 (m, 2H) 3.90 (t, J=6.78 Hz, 1H) 3.27 (d, J=6.72 Hz, 2H). MS (ESI) m/z 173.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]=[C:10]2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C>[Br:33][C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][C:3]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:2]([F:1])[CH:7]=2)[C:10]([CH2:17][CH2:18][CH3:19])=[N:11][C:12]=1[CH3:16]
Reactant: BrBr
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)c(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a mixture of 2′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.78 g), sodium acetate (0.19 g) and acetic acid (10 mL) was added bromine (0.12 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.54 g, 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:16][CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)=[C:30]([C:37]([F:38])([F:39])[F:40])[CH:29]=1
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CCC[C@H]2N4CCC3)c(C(F)(F)F)c1
Yield: 92.9 %

Procedure:
Tert-butyl (±)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate (56 mg, 91%) was prepared by the general method of Example 319, step A from tert-butyl (±)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate (50 mg, 0.12 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid (54 mg, 0.25 mmol) as a white foam. MS (ESI): 503.6 (base, M+H).