Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Product: O=C(Cc1ccc(F)cc1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(4-fluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.60-8.53 (m, 1H), 8.42-8.35 (m, 1H), 8.15-8.07 (m, 1H), 8.05-7.95 (m, 3H), 7.84-7.76 (m, 1H), 7.72-7.66 (m, 2H), 7.35-7.29 (m, 2H), 7.17 (t, J=8.9, 2H), 3.67 (s, 2H); MS (APCI+) M/Z 438 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.CCO.[Cl-].[NH4+]>C1COCC1.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: N#Cc1ccc([N+](=O)[O-])c2cccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N)c2cccnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Compound 464B (6.00 g, 30.1 mmol) was dissolved in THF (150 mL) at reflux with mechanical stirring. EtOH (150 mL) was then added followed by aqueous ammonium chloride (2.4 g/225 mL water). The mixture was heated at 70° C. and then iron powder (325 mesh, 6.75 g, 120 mmol) was added with vigorous mechanical stirring. After 1 h, the reaction was cooled to 22° C. and filtered through Celite rinsing with methylene chloride. The filtrate was then concentrated to ˜250 mL and the pH was adjusted to 10 by addition of 1N NaOH. The solution was then extracted with ethyl acetate (5×150 mL). The combined organic layers were washed once with brine (250 mL) and then dried over anhydrous magnesium sulfate. Concentration in vacuo gave 5.09 g (100%) of compound 464C as a yellow solid. HPLC: 99% at 1.143 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 170.16 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1cccc(Cl)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 17 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 3-chlorophenyl isocyanate gave the titled compound in 17% yield as white foam. MS: 463.2 (MH+, Cl).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH3:27])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:29]([O:32][CH2:33]I)(=[O:31])[CH3:30].O.C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH3:27])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:33][O:32][C:29](=[O:31])[CH3:30])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OCI
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CC1=C(C(=O)OCOC(C)=O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.2 g) in N,N-dimethylformamide (25 ml) was added dropwise a solution of iodomethyl acetate (1 g) in N,N-dimethylformamide (3 ml) below 5° C. in the course of 2 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (50 ml), and the separated aqueous solution was extracted with ethyl acetate (30 ml). The combined ethyl acetate solution was washed twice with 5% aqueous sodium bicarbonate and twice with an aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and collected by filtration to obtain acetoxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.6 g), mp 78°-83° C.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[S:12][C:8]=2[C:7]([C:23](O)=[O:24])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH2:32][NH2:33].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>O.CN(C)C=O>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH2:32][NH:33][C:23]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[N:10][C:9]=2[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=1)=[O:24]
Reactant: NCc1nccs1
Reactant: Cc1ccc(C(=O)Nc2nc3c(s2)c(C(=O)O)cn3C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)Nc2nc3c(s2)c(C(=O)NCc2nccs2)cn3C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.4 %

Procedure:
Anhydrous N,N-dimethylformamide (30 ml) was added to a mixture of 4-tert-butyl-2-(4-methyl-benzoylamino)-4H-pyrrolo[2,3-d]thiazole-6-carboxylic acid (1.1g, 2.9 mmol), C-thiazol-2-yl-methylamine hydrochloride (0.5 g, 3.3 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 0.4 g, 2.9 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC, 0.9 g, 4.4 mmol), and 4-methyl-morpholine (NMM, 0.8 ml, 7.2 mmol). The resulting solution was stirred at ambient temperature, under N2 blanket, for 15 hours, then slowly poured into 300 ml of rapidly stirred water. Precipitated solid was isolated by filtration, flash chromatographed (silica gel, 100% EtOAc), and then crystallized from ethyl acetate/hexanes to afford 0.9 g (68%) of the product as fine white crystalline powder, mp. 245-246° C. (decomp.). 1H NMR (d6-DMSO): δ 1.72 ppm, s, 9H, 2.40 ppm, s, 3H, 4.73 ppm, d, j=6.0 Hz, 2H, 7.35 ppm, d, j=7.8 Hz, 2H; 7.63 ppm, d, j=3.3 Hz, 1H, 7.74 ppm, d, j=3.3 Hz, 1H, 7.85 ppm, s, 1H, 8.03 ppm, d, j=8.1 Hz, 2H, 8.92 ppm, t, j=6.0 Hz, 1H, 12.49 ppm, s, 1H. MS: M+H=454.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH2:8][O:9][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-hydroxymethyl-3-methylpyridine (1 g, 5 mmol) in N,N-dimethylformamide (50 mL) was added triethylamine (1.56 mL, 15 mmol) and tert-butylchlorodimethylsilane (1.13 g, 7.5 mmol). The mixture was stirred at room temperature for 4 hours, diluted with water (50 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound as a colorless oil (1.51 g, yield 100%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O.[O-2].[Ca+2]>[O-2].[Fe+2].[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5].[O-2].[Ti+4].[O-2].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: CO
Agent: [Fe+2]
Agent: [Ti+4]
Agent: [V+5]
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
o-Cresol, methanol and water in a ratio of 1:2.5:2.5 were reacted in the same way as described in Example 1. The catalyst contained iron oxide, vanadium oxide, titanium oxide and calcium oxide in a molar ratio of 100:22:2:1.5. After working up, 2.6-xylenol was obtained with a selectivity of 98%.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[K+].[Br-]>CCOC(C)=O.CCCCCCC>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1
Yield: 59 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-tert-butoxycarbonyl-piperazin, yield 59% (recrystallized from EtOAc-heptane 1:1). White crystals, m.p. 165–166° C.; 1H NMR (CDCl3) □ 8.45–8.42 (m, 1H), 7.92–7.87 (m, dd-like, 1H), 7.21–7.12 (AB-system, 4H), 7.03–6.98 (m, d-like, 1H), 3.72–3.45 (br m, 8H), 1.49 (s, 9H); 13C-NMR (CDCl3) □ (ref. CDCl3 77.00 ppm):165.71, 154.56, 153.51, 150.21, 148.34, 145.43 (q, J=4.4 Hz), 136.701 (q, J=3 Hz), 123.65 (q, J=271.5 Hz), 122.86, 122.24, 121.62 (q, J=33 Hz), 11.20, 80.32, 44.38, 43.78, 44.6–42.3 (br), 28.36 ppm; IR (KBr) □ 1722 (C═O), 1691(C═O) cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:13]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(Br)c2cccnc12
Solvent: CC#N
Product: Nc1c(Cl)cc(Br)c2cccnc12
Temperature: 75 °C

Procedure:
To a solution of 8-amino-5-bromoquinoline (440 mg, 1.97 mmol) in CH3CN (39 mL) was added N-chlorosuccinimide (250 mg, 1.87 mmol). The mixture was stirred at 75° C. until no further conversion of the starting material was observed by LC/MS and TLC analysis. The mixture was allowed to cool to room temperature then concentrated. The residue was dissolved in EtOAc, then washed with water (2×50 mL) then saturated NaCl (aq) (50 mL). The organic phase was dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 15% EtOAc/hexanes to afford the title compound as a solid: 1H NMR (500 MHz, CDCl3): δ 8.81 (dd, J=1.4, 4.1 Hz, 1H) 8.43 (dd, J=1.4, 8.5 Hz, 1H), 7.71 (s, 1H), 7.51 (dd, J=4.1, 8.5 Hz, 1H); LC6: 4.27 min. (M+H) 259.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].ClN1C(=O)CCC1=O.[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=[CH2:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:11]([C:12]2[CH2:29][CH:28]([CH2:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CCc1ccccc1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(Cc3ccccc3)C2)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.80 g (2.7 mmol) of methyl 2-chloro-3-hydroximinomethyl-4-methylsulfonylbenzoate are dissolved in 20 ml of dimethylformamide with 0.38 g (2.9 mmol) of N-chlorosuccinimide. After stirring at room temperature for 4 hours, 0.49 g (2.9 mmol) of allylbenzene and then 0.29 g (2.9 mmol) of triethylamine are added dropwise at 0° C. After stirring at room temperature for 16 hours, the reaction mixture is concentrated in a rotary evaporator, the residue is dissolved in dichloromethane and the solution is washed with sodium bicarbonate solution and with water. After drying over magnesium sulfate and evaporating the solvent, 1.1 g (100% of theory) of methyl 2-chloro-3-(5-benzylisoxazolin-3-yl)-4-methylsulfonylbenzoate are obtained as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[O:49]1[CH:53]=[CH:52][C:51]([C:54]2[N:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=2)=[CH:50]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:60][C:57]2[CH:56]=[N:55][C:54]([C:51]3[CH:52]=[CH:53][O:49][CH:50]=3)=[CH:59][N:58]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(-c2ccoc2)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccoc3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
A solution of triphenylphosphine (230.0 mg, 0.877 mmol) in methylene chloride (14 mL) cooled to 0° C. was treated with N-bromosuccinimide (160.0 mg, 0.899 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 232.0 mg, 0.701 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-furan-3-yl-pyrazin-2-ylamine (250.0 mg, 1.551 mmol) followed by pyridine (0.12 mL, 1.484 mmol). The resulting reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/2 to 45/55 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-furan-3-yl-pyrazin-2-yl)-propionamide (161.1 mg, 48.5%) as a pale yellow foam: mp 97–101° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H24ClN3O3S2 (M+H)+ 474.1249, found 474.1252.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Fc1cccc(CBr)c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cccc(F)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 42.4 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-fluoro-benzyl bromide (59 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3-fluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (64 mg, 42%) as a white solid. APCI-MS (M+H) 315.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[C:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[N:18][O:19][C:20]=2[CH:21]2[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:21]1([C:20]2[O:19][N:18]=[C:17]([C:24]3[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=3[Cl:30])[C:16]=2[CH2:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
In a cooled (ice bath) 500 mL flask under nitrogen, is added a solution of 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (16 g, 34.3 mmol) in dichloromethane (80 mL). This is followed by dropwise addition of trifluoroacetic acid (80 mL) (added over 30 minutes). The reaction is stirred at room temperature for 90 min. The solvent is removed under vacuum, EtOAc is added (400 mL), and the mixture is washed with 2 N NaOH (2×250 mL) and brine. The organic layer is dried over MgSO4, filtered and evaporated to obtain the title compound as a brown oil (11.78 g, 93%). MS (m/e): 367 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[OH:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Product: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 25 °C
Yield: 15 %

Procedure:
4,6-Dihydroxy-2-methylpyrimidine (1.0 g, 7.9 mmol) was added gradualy to ice-cooled fuming nitric acid (3 ml) stirring. The mixture was stirred for 2 hours cooling with ice and for 1 hour at the room temperature, and then the precipitated crystal was filtered and dried to obtain 207 mg (yield 15%) of 4,6-dihydroxy-2-methyl-5-nitropyrimidine.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][NH:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.[Cl:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[C:23](F)[C:22]=1[Cl:31].O.CN(C)C=O>C(N(CC)CC)C>[Cl:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[Cl:31])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]1[C:17](=[O:19])[NH:27]2
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNC[C@H]12
Temperature: 50 °C
Yield: 157.3 %

Procedure:
To a slurry containing 5.0 g of (R)-4-carbobenzyloxypiperazine-2-carboxylic acid, 4.2 g of 1,2-dichloro-fluoro-5-nitrobenzene, 85 mL of water and 170 mL of dimethylformamide is added slowly 5.3 mL of triethylamine. The solution is heated to 50° C for 5 hours, then at ambient temperature overnight. The dark orange solution is concentrated under reduced pressure (1-2 mm, <50° C.) to an orange oily residue. This oil is dissolved in 400 mL of ethyl acetate and washed with 100 mL of 1 N HCl (2×), with 150 mL of water (2×), and 100 mL of brine. The organic layer is dried over MgSO4, filtered and concentrated to give 8.1 g (94.2%) of title compound as an orange solid foam.
Reaction SMILES: [Cl: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)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C[O:19][C:20]1C2C(=O)C3C(=CC=CC=3)SC=2C(OC)=C[CH:21]=1.N1C=CC=CC=1.C(Cl)(=O)C>CC(C)=O>[C:20]([O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:19])[CH3:21]
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Reactant: COc1ccc(OC)c2c(=O)c3ccccc3sc12
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)Oc1ccc(Cl)c2c(=O)c3ccccc3sc12

Procedure:
1-Chloro-4-hydroxythioxanthone as prepared in Example 1 (13.1 g) and pyridine (1O g) was stirred in acetone (50 ml) at 50°. Acetyl chloride (4.3 g) was added over 0.25 h and the mixture stirred and heated under reflux for a further hour. The mixture was cooled to 20° and quenched with water (150 ml). The resulting solution was extracted with chloroform (50 ml), separated and the organic phase washed twice with water. The organic phase was evaporated to dryness under reduced pressure and the residue crystallised from methanol with a carbon treatment to afford the title compound, 4.1 g (27.0%) as a pale yellow solid of mp 141°-42°. Analysis C15H9ClO3S=304.745 Requires C 59.11% H 2.98% Cl 11.63% S 10.52% Found C 59.10% H 3.06% Cl 11.59% S 10.41%
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[Br:15]Br.S(=O)(O)[O-].[Na+].Cl>ClCCl.O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Br:15][C:7]1[S:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(C)Cc1cccs1
Agent: Cl
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)Cc1ccc(Br)s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To solution of 2-isobutylthiophene (743 mg, 5.30 mmol) in 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (2.3 mL, 2.5 M in hexanes) dropwise. The resulting solution was stirred for 20 minutes at −78° C. Bromine (0.35 mL, 6.89 mmol) was added dropwise as a solution in 1 mL anhydrous dichloromethane. The resulting mixture was stirred at −78° C. for 30 minutes before being poured, while cold, into 50 mL of 5% sodium bisulfite solution. 1 N hydrochloric acid (50 mL) was added and organics were extracted with ether (3×75 mL), washed with 0.1 N hydrochloric acid, water and brine (50 mL each), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (0-10% ethyl acetate in hexanes) to give 2-bromo-5-isobutylthiophene as the major component of a mixture of two compounds. Used without further purification or characterization.
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[NH:10][C:11]1[C:12](=[O:27])[N:13]([CH3:26])[CH:14]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=1.[C:28]([O:31][CH2:32][C:33]1[C:38]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[CH:37][CH:36]=[CH:35][C:34]=1Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C(OCC)C.O.COCCOC>[C:28]([O:31][CH2:32][C:33]1[C:34]([C:15]2[CH:16]=[C:11]([NH:10][C:2]3[CH:3]=[C:4]4[N:9]([N:1]=3)[CH2:8][CH2:7][O:6][CH2:5]4)[C:12](=[O:27])[N:13]([CH3:26])[CH:14]=2)=[CH:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:50][CH2:49][N:48]2[C:41](=[CH:42][C:43]3[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=32)[C:40]1=[O:53])(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 130 °C
Yield: 78.2 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 175a (120 mg, 0.31 mmol), 167f (130 mg, 0.3 mmol), 1,2-dimethoxyethane (4 mL) and 1M aqueous sodium carbonate (1 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (18 mg, 0.02 mmol) was added. The mixture was heated in microwave to 130° C. for 10 min. After this time, 1 acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with 1 acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-60:35:5 CH2Cl2:diethyl ether:methanol to afford a 74% yield (140 mg) of 175b