Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:42][C:43]([C@@H:45]([NH:50][C:51](=[O:54])[O:52][CH3:53])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]([OH:41])[CH2:10][C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:55][S:56]([CH3:58])=O.C(O)(=O)C.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C@H:8]([NH:42][C:43](=[O:44])[C@H:45]([C:46]([CH3:47])([CH3:48])[CH3:49])[NH:50][C:51]([O:52][CH3:53])=[O:54])[C@@H:9]([O:41][CH2:55][S:56][CH3:58])[CH2:10][C@@H:11]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)OCSC)C(C)(C)C
Yield: 59.6 %

Procedure:
A solution containing the product of Example 10E (1.71 g, 2.3 mmol) in DMSO (3.3 g, 42.3 mmol) was treated with acetic acid (4.1 g, 69 mmol) and acetic anhydride (2.35 g, 23 mmol) at 25° C. for 3 days. Excess ice was added to the mixture which was then made alkaline with 10% sodium carbonate. The mixture was extracted with ethyl acetate, the organic layer was separated, washed with 10% sodium carbonate, water (3×), brine, and dried over sodium sulfate. The solvents were evaporated, and the product was purified by chromatography on silica gel eluting with 30-100% ethyl acetate/dichloromethane to give the title compound (1.1 g, 60% yield).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]([OH:38])(=O)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[N:34]1[CH:33]=[CH:32][C:31]([C:30]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:38])=[CH:36][CH:35]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1ccncc1
Agent: Cl
Product: CN(C(=O)c1ccncc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with isonicotinic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-pyridylcarbonyl)-N-methyl-(D)phenylalanyl-(L)-tryptophan; FAB-MS m/e 471 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4]2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1

Procedure:
To a solution of 100 mg (0.23 mol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole in 16 ml of dioxane and 4 ml of water, 90 mg (0.46 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 52 mg (0.046 mmol) of palladium tetrakis and 150 mg (0.46 mmol) mg of cesium carbonate were added successively. The mixture was submitted to microwave irradiation at 120° C. for 30 minutes in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash-chromatography on a silica gel column (CH2Cl2—CH3COCH3) 78 mg (88%) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:7](=[O:8])[O:6][CH2:5][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyltin (1200 g, 3.6 mol), palladium tetrakis triphenylphosphine (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L). The mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100° C. for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated. The resulting solid was purified by silica gel column chromatography (heptane:ethyl acetate, 0->40%) to provide 5-allyl-2-benzofuran-1(3H)-one.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][C:14]([CH3:58])([CH2:56][CH3:57])[CH2:15][C:16]1[N:17]=[C:18]([CH2:40][CH:41]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[CH:45][CH:44]=2)O)[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1.C1(P([N:73]=[N+:74]=[N-:75])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:73]([CH:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)=[CH:47][CH:48]=1)[CH2:40][C:18]1[N:19]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[C:16]([CH2:15][C:14]([CH3:13])([CH3:58])[CH2:56][CH3:57])[N:17]=1)=[N+:74]=[N-:75]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N=[N+]=[N-])c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (72 μL, 0.46 mmol) was added to an ambient temperature solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (140 mg, 0.23 mmol), diphenylphosphoryl azide (0.1 mL, 0.46 mmol) and triphenylphosphine (150 mg, 0.57 mmol) in tetrahydrofuran (5 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 2-(4-{1-azido-2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]ethyl}phenyl)-5-fluoropyridine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[C:16]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:17]2=[N:18][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][C:17]3=[N:18][CH:19]=[C:14]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:1]([OH:3])=[O:2])[CH:15]=[C:16]3[CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 95 °C
Yield: 29.8 %

Procedure:
3-Carboxyphenylboronic acid (700 mg, 4.22 mmol), 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (750 mg, 2.57 mmol), Pd(Ph3P)4 (30 mg, 0.026 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) were combined in dioxane (20 mL) and water (4 mL). The mixture was evacuated/backfilled with nitrogen (3×). The reaction was heated to 95° C. under N2 (g) overnight. The mixture was partitioned between EtOAc and 1 N HCl. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a brown solid which was triturated with Et2O to give the expected product 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (255 mg, 30% yield) consistent by LCMS. LC-MS retention time: 1.83 min; m/z (MH+): 334. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:24])[CH:18]=1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 g, 1.20 mol), and TEA (250 g, 2.5 mol) in DCM (3500 mL) was added 6-chloropyrimidine-4-carbonyl chloride (190 g in 100 mL of DCM) slowly at −60° C. over 1 h. After addition, the mixture was then allowed to warm to 10° C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (1.5 L). The organic phase was collected, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined crude product weight of 800 g, 49% yield. 1H NMR (400 MHz, MeOD-d4) δ 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.0 Hz, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.5 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:16]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:16]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: COC/C=C/c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A mixture of tert-butyl 9-[(1E)-3-methoxypropa-1-ene-1-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (90.0 mg, 0.282 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (60.0 mg, 83.4%) as a solid.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][O:6][C:7]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([CH2:57][CH:58]([CH:68]=O)[CH2:59][CH2:60][CH2:61][CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH:42]=[C:43]([F:56])[C:44]=1[O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48]>>[F:38][C:39]1[CH:40]=[C:41]([CH:42]=[C:43]([F:56])[C:44]=1[O:45][Si:46]([CH:47]([CH3:49])[CH3:48])([CH:50]([CH3:52])[CH3:51])[CH:53]([CH3:54])[CH3:55])[CH2:57][CH:58]([CH:68]=[CH:9][C:8]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:7]=1[O:6][CH2:5][C:4]1[CH:34]=[CH:35][CH:36]=[CH:37][C:3]=1[Cl:2])[CH2:59][CH2:60][CH2:61][CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64]
Reactant: Fc1ccc(OCc2ccccc2Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)CCCCC(C=O)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Agent: [Br-]
Product: CCOC(=O)CCCCC(C=Cc1cc(F)ccc1OCc1ccccc1Cl)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1

Procedure:
Reaction in analogy to Example 21A of [2-(2-chlorobenzyloxy)-5-fluorobenzyl]tri-phenylphosphonium bromide and ethyl 7-(3,5-difluoro-4-triisopropylsilanyloxyphenyl)-6-formylheptanoate results in the title compound with 70% of theory as E/Z mixture (2:1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([C:13]2[O:17][N:16]=[C:15]([CH2:18]OS(C)(=O)=O)[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:47])[C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[C:43]([F:46])([F:45])[F:44])[CH2:31][CH2:30]1)=[O:28].O>CN(C=O)C>[F:42][C:40]1[CH:39]=[CH:38][C:37]([C:43]([F:45])([F:44])[F:46])=[C:36]([CH:41]=1)[C:35]([N:32]1[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][NH:25][CH2:18][C:15]2[CH:14]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:17][N:16]=2)[CH2:30][CH2:31]1)=[O:47]
Reactant: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNCc1cc(-c2ccccc2)on1)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 40 °C
Yield: 18 %

Procedure:
K2CO3 (121 mg, 0.87 mmol) was added to a stirred solution of methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester (120 mg, 0.43 mmol) and 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (162 mg, 0.43 mmol) in DMF (2 mL). The resulting mixture was heated at 40° C. for 1 hr. Cold water was then added and the resulting precipitate was isolated by filtration. The crude solid was purified by preparative HPLC [(Column-AV/SP/C18-25/003, mobile phase-0.1% TFA in water (A)/acetonitrile (B), flow: 6 mL/min, gradient: (Time): (% B)-0:20; 2:20; 10:70)]) to afford 38 mg (17.64% yield) of 1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-[(5-phenyl-isoxazol-3-ylmethyl)-amino]-ethanone. LCMS Purity: 91.95%. 1H NMR (CDCl3): δ 7.94-7.64 (m, 3H), 7.56-7.4 (m, 3H), 7.2 (m, 1H), 7.3 (d, 1H), 6.64-6.48 (d, 1H), 4.0-3.9 (d, 2H), 3.9-3.8 (m, 1H), 3.76-3.56 (m, 2H), 3.56-3.4 (m, 4H), 3.56-3.26 (bs, 1H), 3.2 (d, 2H), 2.49-2.29 (bs, 1H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:8]([NH:32][C:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:7]=1)=[O:5].CC(C)([O-])C.[K+].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:34]([C:33]1[NH:32][C:8]2[C:9]([CH:10]=1)=[CH:30][CH:31]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCC(=O)Nc1cc(C(=O)OC)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of [4-methoxycarbonyl-2-(n-dodecanamido)benzyl]triphenylphosphonium bromide (23.8 g) and potassium tert.-butoxide (3.9 g) were added to dry toluene (680 ml). The stirred mixture was heated to reflux for 15 minutes and cooled to room temperature. Ethyl acetate (1.5 liter) and saturated brine (750 ml) were added; the mixture was shaken and the organic phase separated. The organic extract was dried over magnesium sulphate and was evaporated in vacuo to give an oil. The oil was purified by chromatography on a silica column using chloroform as eluant to give a crude solid which was recrystallised from methanol to give methyl 2-(n-undecyl)indole-6-carboxylate (4.1 g) as an off-white solid, m.p. 83°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][CH:6]=1)=[O:4].[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:13](=[O:14])[C:12]([Cl:17])([Cl:16])[Cl:11])[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1C

Procedure:
WO 00/71129 describes the preparation of 1,4-dihydro-5-alkyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates, key intermediates in the synthesis of pyrrolotriazine carboxamide and benzamide compounds of formula I, by reacting a Michael acceptor such as methyl crotonate with an anion of tosylmethyl isocyanide (TosMIC) to give 4-methylpyrrole-3-carboxylic acid methyl ester. The resulting 4-methylpyrrole-3-carboxylic acid methyl ester is acylated with trichloroacetyl chloride in the presence of aluminum chloride to afford 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester. Treatment of 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester with sodium methoxide produces 3-methylpyrrole-2,4-dicarboxylic acid methyl ester. N-amination of 3-methylpyrrole-2,4-dicarboxylic acid methyl ester using an aminating reagent such as diphenyl phosphoryl hydroxylamine affords 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester. Finally, reaction of 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester with formamide at elevated temperature gives 1,4-dihydro-5-methyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (Hunt, J. T.; Bhide, R. S.; Borzilleri, R. M.; Qian, L. WO 00/71129, Nov. 30, 2000). Although a number of 1,4-dihydro-5-substitued-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates can be prepared by this method, this process is limited due to its lengthy chemical transformations, the use of hazardous aminating reagents and expensive chromatographic separation of products. WO 02/40486 describes an improved synthesis of 3-methylpyrrole-2,4-dicarboxylates by condensing ethaldehyde and isocyanoacetates in the presence of DBU. The synthesis is shorter, however, generation of the side-product, cyanide, is a safety concern. Preparation of 6-ethyl-1,2,4-triazin-5-one by Raney nickel mediated desulfurization of 6-ethyl-1,2,4-triazin-5-one-3-thione has been reported (Taft, W. E.; Shepherd, R. G. J. Med. Chem. (1967), 10, at 883).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](O)=O)[CH2:10]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.COC1C=CC(C[S:33][C:34]2[CH:35]=[C:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:37]=[CH:38][C:39]=2[NH2:40])=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:41]1([C:36]2[CH:37]=[CH:38][C:39]3[N:40]=[C:14]([CH:11]4[CH2:12][CH2:13][CH:9]([NH2:8])[CH2:10]4)[S:33][C:34]=3[CH:35]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Reactant: COc1ccc(CSc2cc(-c3ccccc3)ccc2N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCC(c2nc3ccc(-c4ccccc4)cc3s2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a suspension of (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (35.7 mg, 0.156 mmol) in DMF (1 mL) was added DIPEA (0.082 mL, 0.47 mmol), 3-((4-methoxybenzyl)thio)-[1,1′-biphenyl]-4-amine (50 mg, 0.16 mmol) and HATU (89 mg, 0.23 mmol). The reaction was stirred rt for 16 h. The mixture was concentrated, and the residue was dissolved in DCM and washed with 1 N HCl and water. The organics were combined and dried over Na2SO4 and concentrated. TFA (1 mL) was added to the residue and the solution was heated at 100° C. for 15 min in microwave. The reaction was heated at 60° C. for 16 h. The reaction was concentrated and dissolved in ACN and purified by Prep HPLC (5-90% B over 12 min, Column: PHENOMENEX® Luna Axia 5 u C18 30×100 mm; Solvent A: 10% ACN−90% H2O-0.1% TFA; Solvent B: 90% ACN−10% H2O-0.1% TFA, flow rate=40 mL/min) to give Intermediate 47 (22 mg, 48%) as a white solid. LC-MS (ESI) 295.0 (M+H), RT=1.86 min (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.S([N:36]=[N+:37]=[N-:38])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:36]([C:7]1[C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1)=[N+:37]=[N-:38]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N=[N+]=[N-])cnc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10 g, 32.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Sec-Butyllithium ( 54.8 mL, 1.3M/cyclohexane, 71.4 mmol.) was then added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g, 81.2 mmol.) in THF (100 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and warmed to RT. This mixture was extracted with hexanes (2×200 mL) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 100% hexanes) to afford 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a mixture with starting material (10.2 g). This mixture was directly used in next step. B. 5-Azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 4.6 mmol) was dissolved in ethyl acetate (100 mL) and Pd/C (10%, 100 mg) was added. This suspension was stirred at RT and under 1 atmosphere. of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to afford 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (730 mg, 43.5%, 2 steps). C. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (10.2 g, 31.5 mmol) was diluted in ethyl acetate (200 mL) and acetic acid (100 mL). Zinc dust (50 g, 0.8 mol.) was added in small portions at RT. After stirring the suspension at RT for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×300 mL). The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (6.38 g).