Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:9]=1
Reactant: CCCn1cc(-c2ccncc2)cc([N+](=O)[O-])c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCCn1cc(-c2ccncc2)cc(N)c1=O
Reaction time: 6 h

Procedure:
A solution containing 15.1 g. of 3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone in 400 ml. of dry dimethylformamide was charged into an 800 ml. Parr bottle with 1.5 teaspoons of Raney nickel and the mixture was shaken under 650 p.s.i of hydrogen at room temperature for four hours, during which time the reaction temperature was no more than 50° C. The catalyst was filtered off; the filtrate was treated with decolorizing charcoal and filtered; and, the solvent was distilled off under reduced pressure to leave 12.7 g. of crystalline solid. The solid was recrystallized from methanol to yield 7.2 g. of crystalline 3-amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 171°-173° C. after drying at 70° C. and 0.001 mm. for six hours.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(F)c(C)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(F)c(C)c(Br)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a solution of 1-(5-fluoro-2-hydroxy-4-methylphenyl)ethanone (2.2 g, 13 mmol) and acetic acid (20 mL, 400 mmol) was added N-bromosuccinimide (2.8 g, 16 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. Purification on silica gel with ethyl acetate/hexanes (0-50%) gave 1-(3-Bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone (2.3 g, 71%). 1H NMR (400 MHz, CDCl3): δ 12.80 (s, 1H), 7.40 (m, 1H), 2.60 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])=[O:3].[CH3:17][NH:18][CH3:19]>C(OCC)C>[CH3:17][N:18]([CH3:19])[C:2](=[O:3])[O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8]
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)Cl
Reactant: CNC
Solvent: CCOCC
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)N(C)C
Reaction time: 2 h

Procedure:
To a solution of (97%) 1,3-dimethyl-3(t-butylperoxy)butyl chloroformate 5.2 g. (0.02 mole) in diethyl ether, cooled to 0°±1° C. was added a solution of dimethylamine, 1.8 g. (0.04 mole) in diethyl ether over a period of 10 minutes. After the addition was complete the mixture was allowed to stir for two hours while the reaction temperature was allowed to rise to 20°±1° C. The reaction mixture was then filtered to remove the amine hydrochloride and the organic phase washed with 10% aqueous Tartaric acid solution and water to neutrality.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([C:22]2([Cl:25])[CH2:24][CH2:23]2)=O)=[CH:14][CH:13]=1.[OH-].[K+].OO>C(O)(C)(C)C>[Cl:25][C:22]1([C:20]2([CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:10][O:9]2)[CH2:23][CH2:24]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: Clc1ccc(CCC2(C3(Cl)CC3)CO2)cc1
Temperature: 30 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
16 ml (0.22 mol) of dimethyl sulphide and 24.2 g (0.19 mol) of dimethyl sulphate are added to 30 ml of tert.-butanol and the mixture is allowed to stand for 14 hours at 20° C. A solution of 17 g (0.07 mol) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone in 70 ml of tert.-butanol is initially added dropwise with stirring to the reaction mixture and 22 g of potassium hydroxide powder are then introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 50 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted using ethyl acetate. The organic phase is washed using water and is concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 13.4 g (75% of theory) of 2-(1-chlorocyclopropyl)-2-(4-chlorophenylethyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR69##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[CH3:40][CH2:41][N:42]=[C:43]=[N:44][CH2:45][CH2:46][CH2:47][N:48](C)C.NCCCN1C=CN=C1>ClCCl>[N:44]1([CH2:45][CH2:46][CH2:47][NH:48][C:35]([C:34]2[CH:38]=[CH:39][C:31]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:32][CH:33]=2)=[O:37])[CH:40]=[CH:41][N:42]=[CH:43]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: NCCCn1ccnc1
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(C(F)(F)F)cc2)nc2c(c1-c1ccc(C(=O)NCCCn3ccnc3)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 20 %

Procedure:
To a stirred solution of 4-((9aS)-3-(ethoxycarbonyl)-5-oxo-2-{2-[4 (trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl)benzoic acid) Example 4C (0.050 g, 0.102 mmol) in 1 mL of dichloromethane, EDCI (0.023 g, 0.123 mmol) and 1-(3-aminopropyl)imidazole (0.026, 0.205 mmol)were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 10 mL ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 (2×) and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography (dichloromethane/methanol (10:1)) to yield 0.013 g (20%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.89 (s, 2H), 7.52–7.50 (d, 2H, J=8.1), 7.39–7.37 (d, 2H, J=7.9), 7.32–7.29 (d, 2H, J=8.1), 7.89–6.89 (m, 2H), 4.73–4.70 (dd, 1H, J=6.4, J=10.3), 4.25 (bs, 2H), 4.04–3.92 (m, 2H), 3.72–3.60 (m, 1H), 3.52 (bs, 2H), 3.40–3.31 (m, 2H), 3.27–3.18(m, 4H), 2.51–2.41(m, 1H), 2.40–2.28 (m, 2H), 2.25–2.11 (m, 2H), 1.43–1.29 (m, 1H), 1.22 (s, 1H), 0.889–0.853 (t, 2H, J=7.2); low resolution MS (ES+) m/e 646 (MH+); TLC (CH2Cl2/MeOH (9:1)): Rf=0.24; RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=8.12 min, 96.6% purity.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[C:9]1([P:15](Cl)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][P:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Cc1noc(NP(=O)(c2ccccc2)c2ccccc2)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)diphenyl phosphinic amide was prepared by the method of Example 1 with 3,4-dimethyl-5-amino isoxazole (0.22 g, 2.0 mmol), diphenyl phosphinic chloride (0.6 ml, 3.0 mmol) and pyridine (5 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from ethyl acetate and hexanes provided 0.38 g (61%) of white crystals, m.p. 167-170° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C:37]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)([C:40](O)=[O:41])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([C:37]2([C:40]([N:25]3[CH2:26][CH2:27][N:22]([C:20]4[C:21]5[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=5[N:17]=[CH:18][N:19]=4)[CH2:23][CH2:24]3)=[O:41])[CH2:38][CH2:39][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:34])[CH2:36]2)=[CH:48][CH:47]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)C4)CC3)c21
Reaction time: 8 h
Yield: 58 %

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (26.9 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred overnight, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), eluted by a mixture of MeOH and CH2Cl2 (1.5:98.5) to give tert-butyl 3-(4-chlorophenyl)-3-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate as a clear oil (25 mg, 69%). LCMS (APCI+) [M-Boc+H]+526.1; Rt: 3.49.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC[B-](F)(F)F
Reactant: O=Cc1cc2cc(Br)ccc2[nH]1
Agent: [K+]
Product: CCCCc1ccc2[nH]c(C=O)cc2c1
Yield: 27.8 %

Procedure:
5-Butyl-1H-indole-2-carbaldehyde was synthesized as in Example 3.1 using 5-bromo-1H-indole-2-carbaldehyde (300 mg, 1.34 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (352 mg, 2.21 mmol) in place of hexylboronic acid to give 5-butyl-1H-indole-2-carbaldehyde (75 mg, 28%). Used without further characterization.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:33])[C:19](=O)[C:20]=1[NH:21][C:22]1[C:30]2[NH:29][C:28](=[O:31])[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1)C>>[CH3:1][C:2]1[O:6][C:5]([CH:7]([NH:13][C:19]2[C:18](=[O:33])[C:17](=[O:16])[C:20]=2[NH:21][C:22]2[C:30]3[NH:29][C:28](=[O:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2cccc3[nH]c(=O)[nH]c23)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Product: Cc1ccc(C(Nc2c(Nc3cccc4[nH]c(=O)[nH]c34)c(=O)c2=O)C2(C)COC2)o1
Temperature: 65 °C
Yield: 18 %

Procedure:
0.33 g of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (1.80 mmol, 1.2 eq) was added to a solution of 0.41 g of 3-ethoxy-4-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-ylamino)cyclobut-3-ene-1,2-dione (1.50 mmol, 1 eq). The reaction medium was heated at 65° C. for 18 hours. The methanol was evaporated off and the residue was chromatographed on silica gel, eluent 95/5 dichloromethane/methanol with 0.1% of triethylamine. The product remains stuck on the silica. The paste obtained was crystallized from diethyl ether, filtered and dried under vacuum at 40° C. 0.11 g of 3-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-4-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-ylamino)cyclobut-3-ene-1,2-dione was obtained. Yield=18%. HPLC 94.8%, ES− [407].
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([C:21]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)([CH3:23])[CH3:22])[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([C:21]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)([CH3:23])[CH3:22])[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(C(C)(C)c4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(c1ccc2ncccc2c1)n1nnc2ccc(-c3ccc(C(=O)O)c(F)c3)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a solution of Example 82 (0.700 g, 1.60 mmol) in methanol (3.7 ml), lithium hydroxide (0.626 g, 14.94 mmol) in water (3.7 ml) and THF (14 ml) were added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.485 g, 71%) MS (m/z): 472.99 (M+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([NH:35][CH2:36]C4C=CC=C(C(F)(F)F)C=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:47][C:48]([F:58])([F:57])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52]N>>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([NH:35][CH2:36][CH2:52][C:51]4[CH:54]=[CH:55][CH:56]=[C:49]([C:48]([F:58])([F:57])[F:47])[CH:50]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared by the route used to prepare 3-(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylamino)pyridin-2-yl)phenylcarbamoyl)benzylthio)propanoic acid 69, substituting 3-(trifluoromethyl)phenethylamine for 3-(trifluoromethyl)benzylamine. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 13.37 (s, 1H), 12.23 (s, 1H), 8.22 (s, 1H), 7.82-7.74 (m, 2H), 7.64-7.50 (m, 6H), 7.12 (m, 3H), 6.99 (s, 1H), 6.70 (s, 1H), 3.82 (s, 2H), 3.47 (s, 2H), 3.21 (t, 4H), 2.92 (t, 2H), 2.58-2.50 (m, 4H), 1.66 (m, 4H), 1.58 (m, 2H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:31]([CH3:33])[CH3:32])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[C:18]3[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]#[N:14])=[CH:8][CH:7]=2.[N-:34]=[N+:35]=[N-:36].[Na+].Cl>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[F:28][C:26]([F:29])([F:27])[C:25]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([C:4]3[C:3]([N:2]([CH:31]([CH3:33])[CH3:32])[CH3:1])=[N:12][C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:13]5[NH:36][N:35]=[N:34][N:14]=5)[CH:10]=4)[N:5]=3)[CH:16]=2)[NH:20][C:19]=1[CH3:24])=[O:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1[nH]c2ccc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)cc2c1C(=O)C(F)(F)F
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1[nH]c2ccc(-c3nc4ccc(-c5nnn[nH]5)cc4nc3N(C)C(C)C)cc2c1C(=O)C(F)(F)F
Yield: 22.3 %

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-[2-methyl-3-(2,2,2-trifluoroacetyl)-1H-indol-5-yl]quinoxaline-6-carbonitrile (160 mg, 0.35 mmol) in DMSO (20 ml) was added ZnBr2 (38 mg, 0.17 mmol) and NaN3 (91 mg, 1.40 mmol) in water (2 ml). The resulting solution was heated to reflux overnight and diluted with water (200 ml), adjusted to pH 3 with HCl (2N), extracted with ethyl acetate (5×50 ml), and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (15% dichloromethane in methanol) to afford 2,2,2-trifluoro-1-(5-(3-(isopropyl(methyl)amino)-6-(1H-tetrazol-5-yl)quinoxalin-2-yl)-2-methyl-1H-indol-3-yl)ethanone as a yellow solid (38.6 mg, 27%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:13]([CH2:19]C=C)[C:14]([O:16]CC)=O)[C:4](C=C)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH:34]([CH3:36])[CH3:35])=[C:32]([NH2:37])[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:33]([CH:34]([CH3:35])[CH3:36])=[C:32]([NH:37][C:14](=[O:16])[C@@H:13]([N:3]3[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]3[CH3:1])[CH3:19])[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: CC(C)c1c(N)cnn1-c1ccc(Cl)cc1
Reactant: C=CCC(C(=O)OCC)n1c(C)nc(C(F)(F)F)c1C=C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)Nc1cnn(-c2ccc(Cl)cc2)c1C(C)C
Reaction time: 0.58 h

Procedure:
To a solution of the acid intermediate from step d (23.6 mg, 0.1 mmol) and 1-(4-chlorophenyl)-5-isopropyl-1H-pyrazol-4-amine (16.6 mg, 0.064 mmol) in DMF (0.5 mL) was added Et3N (20 μL, 0.13 mmol) and HATU (31.6 mg, 0.083 mmol). After stirring 35 min, the slurry was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent). The residue was neutralized and salted with HCL to provide the titled compound hydrochloride salt as a colorless solid (12.3 mg). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=1.6 Hz, 1H), 7.63 (s, 1H), 7.57 (ddd, J=9.7, 5.1, 3.1 Hz, 2H), 7.41 (ddd, J=9.7, 5.0, 3.1 Hz, 2H), 5.38 (q, J=7.0 Hz, 1H), 3.03 (hept, J=7.0 Hz, 1H), 2.65 (s, 3H), 1.91 (d, J=7.0 Hz, 3H), 1.23 (d, J=7.1 Hz, 3H), 1.22 (d, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C20H22ClF3N5O [M+H]+ 440.1, found 439.9. Retention time on chiral HPLC: 5.9 min (RegisPack cat#783104, 25 cm×4.6 mm, 5 micron; eluent: 0.1% diethylamine/IPA, 1.0 ml/min). The er is determined to be 20:1 with the (R)-enantiomer having a retentime of 3.4 min. Absolute configuration of the (R)-enantiomer was confirmed by an independent synthesis from methyl (L)-lactate.
Reaction SMILES: CC[O:3][C:4]([C:6]1([CH3:17])[CH2:9][CH2:8][N:7]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:5].[OH-].[Na+]>CCO>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:6]1([CH3:17])[C:4]([OH:5])=[O:3])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1(C)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC1(C)C(=O)O
Temperature: 20 °C
Reaction time: 15 h
Yield: 89.7 %

Procedure:
To a solution of 2-methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (63 g, 1 eq.) in 260 mL of EtOH was added 260 mL of an aqueous solution of NaOH 2N (2 eq.). The reaction was stirred at 20° C. for 15 h. The solvent was removed under reduced pressure and the crude was partitioned between water and EtOAc. The organic layer was discarded and the aqueous layer was acidified by addition of a solution of citric acid 10% in water until pH=5 and thoroughly extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester (50 g, yield=89%).
Reaction SMILES: Cl.NO.[CH:4]([C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1)=[O:5].C([O-])(=O)C.[Na+]>CO.O>[OH:5][CH2:4][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2CO)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 4 h
Yield: 14.4 %

Procedure:
Hydroxylamine hydrochloride (33 mg, 0.5 mmol) was added to a stirred cold (0° C.) mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (150 mg, 0.4 mmol) and sodium acetate (65 mg, 0.8 mmol) in MeOH (3 mL) and stirring was continued at ambient temperature for 4 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 25 mg (58% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-hydroxymethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 435.2, 93.8%, 1H NMR (300 MHz, DMSO-d6): δ8.3 (s, 1H), 8.2 (b, 1H), 7.8 (d, 2H), 7.7 (d, 1H), 7.5 (t, 2H), 7.4 (t, 2H), 7.2 (d, 2H), 7.0 (t, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+:15].[K+]>CO>[K+:15].[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C([O-])c1ccccc1Br
Yield: 100 %

Procedure:
To a solution of o-bromobenzoic acid (201.03 g, 1.0 mol) in MeOH (500 mL), K2CO3 (69 g, 1.0 mol) was added. The mixture was concentrated to give the desired product (239.1 g, 1.0 mol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH2:22][CH:21]4[NH:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)C(C1C=CC2C(=C3CC4NC(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:16]3[CH2:22][CH:21]4[NH:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Product: Brc1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2

Procedure:
Using an adaptation of the method described in Procedure 9, substituting 3-(3-bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane, 1b for 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 8a, the title compound 3-(3-bromo-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 2b was obtained. MS m/z=370.0/372.0 (MH+).