Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:10]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(N[C@@H](C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(N[C@@H](C)c2ccc(F)c(F)c2)c2cccc(N)c2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-[(S)-1-(3,4-difluorophenyl)ethyl]amine (1.50 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (1.79 g) and sodium borohydride (600 mg) were reacted, and the reaction mixture was purified by chromatography through a silica gel column using a 1:8 by volume mixture of ethyl acetate and toluene as the eluant, to afford isomer A (199 mg) as a yellow oil and isomer B (290 mg) as a yellow oil of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.P(Cl)(Cl)(Cl)=O.C(O[CH:16](OCC)[C@@H:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:18]=[CH:19][C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH:19]1[C:20]2[N:21]([CH:22]=[CH:23][CH:24]=2)[CH:16]=[C:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:18]=1
Reactant: CCOC(=O)[C@@H](N=Cc1ccc[nH]1)C(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2cccc2cn1
Temperature: 65 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
To a hot (65° C.) solution of TFA (44 mL, 510 mmol) and phosphorus oxychloride (39.0 g, 140 mmol) is added drop-wise a solution of ethyl 3-ethoxy-O-ethyl-N-(1H-pyrrol-2-ylmethylene)serinate (Dekhane, M; Potier, P; Dodd, R. H. Tetrahedron, 49, 1993, 8139-46.) (9.6 g, 28.0 mmol) in anhydrous 1,2-dichloroethane (200 mL). The black mixture is allowed to stir at 65° C. for 18 h at which point it is cooled to rt and neutralized with sat. NaHCO3 and solid NaHCO3 to pH ˜9. The phases are separated and the basic phase extracted with EtOAc (4×100 mL). The organic phases are combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give a black oil that is purified with silica gel chromatography (35% EtOAc/heptanes to 50% over several liters) to give a light brown solid for ethyl pyrrolo[1,2-a]pyrazine-3-carboxylate. Yield 24%. HRMS (FAB) calcd for C10H10N2O2+H 191.0820, found 191.0823.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.Cl.[CH3:26][O:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30].CS(C)=O.C(N(CC)CC)C>C(#N)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:30][CH:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([O:27][CH3:26])=[O:38])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C

Procedure:
0.500 g (1.519 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.328 g (1.519 mmol) of L-phenylalanine methyl ester hydrochloride were placed in a 25 ml round bottom flask equipped with a magnetic stirring bar. 3 ml of dimethylsulfoxide was added and the solution was stirred to dissolve as much solid as possible at room temperature. Then 159 mg (1.571 mmol) of triethylamine was added and the solution was stirred at room temperature (20° C.) for one hour. 10 ml of acetonitrile was added to the stirring solution. The solution was triturated with ether until a white precipitate had formed. The solution was filtered to remove the triethylamine hydrochloride. The mother liquor was again treated with ether to produce a precipitate. The mixture was filtered and the white solid was washed with ethyl ether and dried. This yielded 0.465 g of a white solid. The white solid material was added to 22 ml ethanol/H2O 9:1 and was heated to dissolve the compound. After allowing to cool to room temperature, ether was added until just before the cloud point. The solution was placed in a refrigerator overnight. Upon filtration and washing with ether, 0.235 g of 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-3-phenylpropanoic acid, methyl ester (AIT-0085) as a white crystalline material was obtained. m.p. 186°-191° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:27]([CH2:35][C:36](=O)[CH3:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:37]/[C:36](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:35]/[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from a suspension of 113 mg (0.32 mmol) of Intermediate 54 and 52 mg (0.32 mmol) of benzoylacetone to yield 44 mg (28%) of example 54: TLC (DCM/MeOH, 4/1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.43 (d, 1H, J=9.0), 7.92-7.88 (m, 2H), 7.8 (m, 2H), 7.48 (m, 3H), 7.38-7.38 (m, 3H), 7.16 (d, 2H, J=8.4), 6.9 (d, 2H, J=8.4), 5.53 (s, 1H), 4.91 (s, 1H), 4.15 (m, 1H), 3.2 (m, 2H), 2.83-2.74 (m, 1H), 2.37 (s, 3H), 1.67 (s, 3H); low resolution MS (ES+)m/e 497.07 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[C-:30]#[N:31].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.[Cu]I.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>[Cl:28][C:20]1[CH:19]=[C:18]([CH:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:30]#[N:31])=[CH:7][N:6]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2cnc(C#N)cn2)cc1Cl
Temperature: 150 °C
Yield: 75.1 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (prepared as in Example 21, 325 mg, 0.65 mmol) in N,N-dimethylformamide (5 mL) at 25° C. was treated with potassium cyanide (105 mg, 1.62 mmol), copper(I) iodide (307 mg, 1.62 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol), and 18-crown-6 (25 mg, 0.09 mmol). This reaction mixture was then heated to 150° C. under argon for 5 h. At this time, the reaction was cooled to 25° C., concentrated to half the volume, and then chloroform (40 mL) was added until all the salts precipitated out of solution. The salts were removed by filtration through a pad of celite and washed with chloroform. The filtrate was then concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 30/70 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyano-pyrazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide (219 mg, 76%) as a white foam: (ES)+-HRMS m/e calcd for C20H21ClN4O4S (M+H)+ 449.1045, found 449.1046.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33]Br)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][N:8]([CH2:33][CH:31]2[CH2:30][C:29]3[CH:35]=[C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:26]=[CH:27][C:28]=3[O:32]2)[CH2:7][CH2:6]1
Reactant: OC1(Cc2ccc(F)cc2F)CCNCC1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: OC1(Cc2ccc(F)cc2F)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=466.6 (M+H+) was prepared from 4-(2,4-difluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].CCN(C(C)C)C(C)C.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: BrCC1CC1
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1cn(CC2CC2)c2ccc(Br)cc12
Temperature: 50 °C
Yield: 85.9 %

Procedure:
To 5-bromoindole-3-acetic acid (890 mg, 3.5 mmol) in 1-methyl-2-pyrrolidinone (12 mL) at 0° C. were added iPr2NEt (21 mmol) and bromomethylcyclopropane (10.5 mmol). The reaction mixture was heated at 50° C. for 19 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column (30% EtOAc in hexane) yielded 927 mg (86% yield) of the product.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)C1C=CC=CC=1.[BH4-].[Na+].O>C(O)C.OS(O)(=O)=O.C(OCC)(=O)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(C#CCCCOc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: OCc1ccc(CCCCCOc2ccccc2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
4-(5-Phenoxypent-1-ynyl)benzyl alcohol--To a solution of 2.02 g of 4-5-phenoxypent-1-ynyl)benzaldehyde (from step (2) above) in 50 mL ethanol at 0° C. was added 640 mg sodium borohydride. After stirring for 1 hour, then addition of 8 mL water and evaporation of the solvents in vacuo, the residue was diluted with 2% H2SO4 and ethyl acetate. The organic layer was washed with brine and saturated NaHCO3 and then dried and the solvent evaporated in vacuo to give the title compound (99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[NH:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([NH:11][CH3:12])=[C:2]([Cl:1])[C:3]=1[F:16]
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1c([N+](=O)[O-])cc(C(=O)OC)c(F)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 5.30 g (21.32 mmol) of 3-chloro-2-fluoro-4-methylamino-5-nitro-benzoic acid in 53 mL of THF and 13.75 ml of MeOH is cooled to a temperature of 0° C. Then, 13.86 ml (27.72 mmol) of trimethylsilyl-diazomethane (2 M in diethylether) were added portion wise at a temperature of 0° C. The mixture is stirred 30 min at a temperature of 0° C. and 30 min at ambient temperature. The reaction mixture is evaporated with acetic acid in the trap. The yellow residue is titurated in diethyl ether and after decantation, 4.3 g (16.37 mmol, 77%) of a yellow solid is isolated. The Et2O phase is evaporated and 1.5 g of impure product is recovered. The crude product is used directly in the next step without purification. 1H-NMR (CDCl3, 300 MHz): ? ppm=3.30 (d, 3H), 3.95 (s, 3H), 7.80 (s br, 1H), 8.70 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:27])[C@@H:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:5][C@H:6]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]([CH3:9])[CH3:8].[CH3:28][C:29]([CH3:37])([CH2:33][CH2:34][CH2:35][CH3:36])[C:30](O)=[O:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([O:11][CH2:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[CH2:5][C@H:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:3]([OH:27])[CH2:2][NH:1][C:30](=[O:31])[C:29]([CH3:37])([CH3:28])[CH2:33][CH2:34][CH2:35][CH3:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCC(C)(C)C(=O)O
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
To a solution of tert-butyl (2S,3S,5S)-1-amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptan-3-ylcarbamate (500 mg, 1.32 mmol) in CH2Cl2 (15 mL), were added 2,2-dimethylhexanoic acid (220 mg, 1.45 mmol), HOBt (360 mg, 2.65 mmol) and EDCl (500 mg, 2.65 mmol). The mixture was cooled to 0° C. and DIEA (850 mg, 6.6 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel to produce tert-butyl (2S,3S,5S)-5-(benzyloxymethyl)-1-(2,2-dimethylhexanamido)-2-hydroxy-6-methylheptan-3-ylcarbamate (310 mg, 46%); MS: 507 (M++1)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([Br:19])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35].Cl>O1CCCC1>[Br:19][C:16]1[CH:17]=[C:18]2[C:10]([C:8]([C:4]3[C:3]([F:20])=[C:2]([NH:1][S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])(=[O:36])=[O:35])[CH:7]=[CH:6][CH:5]=3)=[O:9])=[CH:11][NH:12][C:13]2=[N:14][CH:15]=1
Reactant: Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(c1cccc(NS(=O)(=O)c2ccccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
To (3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (19, 53 mg, 0.159 mmol) in 0.63 mL of tetrahydrofuran, pyridine (0.115 mL, 1.43 mmol) is added, followed by 2-fluorobenzenesulfonyl chloride (20, 46 mg, 0.238 mmol) and the reaction is stirred at room temperature for 48 hours. Hydrochloric acid (1M aqueous) is added to adjust the mixture to pH 4, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (21, 56 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].II.[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:5]1[CH:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cccc1C=O
Reactant: BrBr
Agent: II
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)cc1C=O
Temperature: -10 °C
Yield: 95.7 %

Procedure:
To a solution of 1-methyl-1H-pyrrole-2-carbaldehyde (1.09 g, 10.0 mmol) in 60 mL chloroform at −20° C. was added a single crystal of iodine. The mixture was stirred until homogeneous. Bromine (0.51 mL, 10.0 mmol) was added dropwise as a solution in 10 mL chloroform. The solution was stirred while warming from −20 to 0° C. over 1.5 h. Chloroform was removed in vacuo and the residue added to 5% sodium bisulfite solution to quench excess bromine/iodine. Saturated sodium bicarbonate was added until the pH of the mixture reached 7. Organics were extracted with ether (3×75 mL), dried over magnesium sulfate, filtered and concentrated to give crude 4-bromo-1-methyl-1H-pyrrole-2-carbaldehyde (1.80 g) as the major component of a mixture of starting aldehyde and dibromopyrrole. Used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]2[C:30]3([CH2:36][O:37][C:26]=2[CH:25]=1)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][C:30]2([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=3[O:37][CH2:36]2)[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC2(CC1)COc1cc(F)ccc12
Yield: 77.8 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.193 g, 0.556 mmol) obtained in Example 22, step 3 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.150 g, 0.616 mmol) obtained in Reference Example 4, the title compound (0.232 g, 77%) was obtained.
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:14]1[CH:13]=[C:12]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.70 g, 6.05 mmol) and methyl urea (673 mg, 9.08 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 17.3 mL, 12.1 mmol) was refluxed at 100° C. for 6 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[2-(3-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (149.1 mg, 8%) as a white solid: mp 52-55° C.; EI-HRMS m/e calcd for C16H21ClN2O2 (M+) 308.1292, found 308.1287. The methyl ester of the starting material was recovered from the reaction mixture due to transesterification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)Cc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of diisopropylamine (8.00 mL, 57.1 mmol) in THF (300 mL) cooled to 0° C. was added n-BuLi (24.60 mL, 61.5 mmol) dropwise. The mixture was stirred at 0° C. for 1 h. Then to the mixture cooled to −30° C. was added a solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF (2 mL). The mixture was stirred at −30° C. for 1 h. To the mixture was added a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g, 43.9 mmol) in THF (5 mL) at −30° C. The whole mixture was stirred at −30° C. for 3 h and then stirred at 25° C. for 12 h. The mixture was quenched with NH4Cl(aq) and extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on silica column chromatography (PE/EA=200:1). All fractions found to contain product by TLC (PE/EA=10:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of ethyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 35.3 mmol, 80.0% yield): 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J=8.0 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s, 6H); ES-LCMS m/z 275 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:59]=[CH:60][CH:61]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]([O:46]CC2C=CC=C(CN3CCC3)C=2)=[O:45])[CH2:25][CH2:24][CH2:23]1.[OH-].[Na+]>O1CCCC1>[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:59]=[CH:60][CH:61]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]([OH:46])=[O:45])[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cccc(CN5CCC5)c4)n3Cc3cccc(CN4CCC4)c3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(CN4CCC4)c3)n12
Reaction time: 1 h

Procedure:
3-(Azetidin-1-ylmethyl)benzyl 6-[3-(azetidin-1-ylmethyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate tris(trifluoroacetate) (0.15 g, 0.17 mmol, from Step 6) was dissolved in tetrahydrofuran (5 mL) and 1.0 M NaOH (5 mL, 5 mmol) was added. The reaction was stirred for 1 hour. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) Yield: (0.033 g, 51%).
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+]>C1COCC1.O>[CH3:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:13])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(=O)O)s1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A solution of (5-methylthiophen-2-yl)-oxo-acetic acid ethyl ester (5.5 g, 28 mmol) in THF (20 ml), water (20 ml), and 50% NaOH (4 ml) was stirred under reflux for 18 hours. The reaction mixture was allowed to cool to ambient temperature. After partial evaporation, the reaction mixture was acidified with 1N HCl and extracted with diethyl ether (2×50 ml). The organic layer was dried over sodium sulfate and concentrated under vacuum to yield (5-methylthiophen-2-yl)-oxo-acetic acid (4.8 g, 100%). 1H NMR (300 MHz, CDCl3) δ8.40 (1H, d, J=4.0 Hz), 6.95 (1H, d, J=3.9 Hz), 2.63 (3H, s).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4])[CH3:2].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:3]([CH2:1][CH3:2])=[O:4])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)CC)n1

Procedure:
A mixture of 4.35 g. 3-ethylsulphinyl-1,2,4-triazole, 6.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was filtered and the filtrate distilled under reduced pressure to remove solvent, giving a residual oil which solidified on cooling. This solid product was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-diallylcarbamoyl-3-ethylsulphinyl-1,2,4-triazole, m.p. 41° - 43°C. Elemental analysis satisfactory.