Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([F:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(O[C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@H:11]([O:12][C:6](=[O:7])[CH3:5])[C@H:10]([F:13])[C@@H:9]([CH2:14][O:15][C:20](=[O:22])[CH3:21])[O:8][CH:6]1[O:7][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](F)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1C(OC(C)=O)O[C@H](COC(C)=O)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-4-fluoro-2,4-dideoxy-D-glucopyranose (1.35 g, 6.048 mmol) in a mixture of pyridine (50 ml) and acetic anhydride (25 ml, 27 g, 264 mmol) was stirred at room temperature for 24 hours at which time no starting material but two close spots appeared by TLC. Stirring continued for another 15 hours. Solvent was then removed by evaporation in vacuo; the residue was now co-evaporated with toluene (4×50 ml) then dried in vacuo. This material was now adsorbed on 5 g of silica gel then placed on a silica gel column (45 g, 20×360 mm) poured in CH2Cl2/acetone (8:1). The column was eluted with 500 ml of CH2Cl2/acetone (8:1) followed by 500 ml of CH2Cl2/CH3OH (7:3). The product and trailing spots eluted immediately, with virtually no separation. The CH2Cl2/CH3OH flush produced a trailing spot. All were evaporated and dried in vacuo.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>C(Cl)Cl>[C:15]1([CH2:14][CH2:13][NH:21][C:10](=[O:12])[CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)CCc1ccccc1I
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1ccccc1I)NCCc1ccccc1
Reaction time: 72 h
Yield: 120.9 %

Procedure:
To a solution of 2-iodobenzenepropionic acid (8 g, 0.029 mol) and phenethylamine (10.9 g, 0.090 mol) in methylene chloride (200 mL) was added N-ethyl-N-[3-(dimethylamino)propyl]carbodiimide hydrochloride (6.13 g, 0.032 mol) at room temperature. After 3 days, water (100 mL) and 2.5N HCl (50 mL) were added. The organic phase was separated, dried and concentrated to give an oil (13.3 g). The oil was chromatographed on silica gel and eluted with hexane: ethyl acetate (2:1) then hexane: ethyl acetate (1:1) to give a fraction containing a yellow solid 7.6 g (69%). Recrystallization from toluene (15 mL) and petroleum ether (150 mL) afforded 7.1 g of product, mp. 94.5°-95.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1cc(Br)ccn1)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Under a stream of nitrogen, 5 g (29.07 mmol) of 4-bromo-2-methylpyridine and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The solution is cooled to 5° C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5° C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 8.4 g (93%) of compound are obtained in the faun of a yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:42])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:35]([CH:37]([CH3:39])[CH3:38])[CH3:36])[C:32](O)=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:40])[N:20]([CH3:41])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH:31]([N:35]([CH:37]([CH3:38])[CH3:39])[CH3:36])[C:32]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)=[O:33])=[CH:29][CH:30]=4)[C:21](=[O:40])[N:20]([CH3:41])[CH:19]=3)[C:13]=2[CH3:42])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)N3CCN(C)CC3)N(C)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a sealed tube equipped with a magnetic stirrer, were charged 29 (100 mg, 0.168 mmol), 1-methylpiperazine (14.6 mg, 0.168 mmol), DMF (3 mL), Hunig's base (65.1 mg, 0.503 mmol), and BOP (74.3 mg, 0.168 mmol). The reaction mixture was stirred at room temperature for 26 hrs. Most solvent was removed by rotary evaporation and the resulting residue was dissolved in ethyl acetate (100 mL). The solution was washed with water (15 mL×3), dried over MgSO4, filtered and solvent removed in vacuo. Silica gel column chromatography (MeOH:CH2Cl2=5:95) afforded 30 as a light yellow solid, 25 mg (22%). 1H NMR (300 MHz, CDCl3) 8.45 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.85 (m, 2H), 7.75 (m, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.40 (m, 2H), 7.19-7.23 (m, 2H), 6.79 (s, 1H), 5.19 (s, 1H), 3.62 (s, 3H), 3.40 (broad s, 2H), 3.21 (broad s, 2H), 2.26-2.50 (m, 9H), 2.18 (s, 3H), 1.92 (broad s, 2H), 1.34 (s, 9H), 1.25-1.31 (m, 6H) ppm; MS (ESI+) m/z 678.19 (M+H).
Reaction SMILES: [CH:1]1([N:7]([CH3:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.[Na].O>CO.[Ni](Br)Br>[CH:1]1([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Agent: Br[Ni]Br
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(N)cc1)C1CCCCC1
Yield: 36.5 %

Procedure:
To a solution of N-cyclohexyl-N-methyl-N-(4-nitrobenzyl)amine (12.4 g, 50.0 mmol) in methanol(250 ml) were added nickel bromide (1.09 g, 5.0 mmol) and then sodium boron hydride (7.57 g, 200 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the mixture were added nickel bromide (0.55 g, 2.5 mmol) and then sodium boron hydride (3.78 g, 100 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water (100 ml), and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and insoluble material was filtered off with Celite. The filtrate was washed with ethyl acetate, and the ethyl acetate layer was dried with MgSO4 and concentrated under reduced pressure. The residue was washed with hexane to give 4-(N-cyclohexyl-N-methylamino-methyl)aniline (3.99 g, 37%). 1H-NMR (200 MHz, CDCl3) δ: 1.0-1.95 (10H, m), 2.17 (3H, s), 2.3-2.55 (1H, m), 3.46 (2H, s), 3.59 (2H, br s), 6.65 (2H, d, J=8.5Hz), 7.10 (2H, d, J=8.5 Hz).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Li+].[OH-]>C1COCC1.CO>[CH3:16][O:15][C:13]([NH:12][CH:4]([CH2:5][CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:17])=[O:2])=[O:14]
Reactant: COC(=O)NC(CC1CCOCC1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)NC(CC1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (0.11 g, 1.1 mmol) in THF (3.3 mL) and MeOH (1.1 mL) at 0° C. (external, ice bath) was added aqueous LiOH (1 M, 0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 18 h and concentrated to provide 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid which was used crude in the next step. LCMS-ESI+: calc'd for C10H17NO5: 231.11 (M+); Found: 231.99 (M+H+).
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:20]([O-:22])=[O:21])=[CH:8][C:9]=2[CH2:15][N:16]2[CH2:18][CH:17]2[CH3:19])[N:4]=1.[BrH:23]>C(O)(=O)C.C(OCC)C>[BrH:23].[O:2]=[C:3]1[C:12](=[O:13])[NH:11][C:10]2[C:5](=[CH:6][C:7]([N+:20]([O-:22])=[O:21])=[CH:8][C:9]=2[CH2:15][N:16]2[CH2:18][CH:17]2[CH3:19])[NH:4]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN3CC3C)c2nc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1CN1Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
180 mg (0.59 mmol) of N-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethyl)-2-methylaziridine are stirred in a 33% solution of hydrogen bromide in acetic acid for 2 hours at 70° C. The mixture is diluted with diethyl ether and the solid is filtered off and washed with diethyl ether. After drying, the title compound is obtained in the form of a yellow solid. M.p.=241° C. (decomp.).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[CH2:8]([CH:10]([C:13]1[N:18]2[N:19]=[C:20]([CH3:23])[C:21](I)=[C:17]2[N:16]=[C:15]([CH3:24])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>C1COCC1.[Zn]>[Cl:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:21]1[C:20]([CH3:23])=[N:19][N:18]2[C:13]([CH:10]([CH2:8][CH3:9])[CH2:11][CH3:12])=[CH:14][C:15]([CH3:24])=[N:16][C:17]=12
Reactant: Clc1ccsc1Br
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sccc3Cl)c(C)nn12
Temperature: 85 °C
Yield: 80.9 %

Procedure:
Suspend Reike® zinc (5 g/100 mL THF, 20 mL, 15.0 mmol) in anhydrous THF (10 mL) and add 2-bromo-3-chlorothiophene (1.98 g, 10.0 mmol). Reflux the mixture under an inert atmosphere in an oil bath (85° C.) for 3 h. Cool the reaction to room temperature and centrifuge the remaining zinc metal. Canulate off the reagent solution into a new vessel under positive argon pressure and add 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.72 g, 5.0 mmol). Degas the solution by positive argon pressure for 10-15 min and add dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium (II) dichloromethane (0.225 g, 0.275 mmol). Stir at reflux temperature overnight under an inert atmosphere. Cool the reaction to room temperature, quench with saturated ammonium chloride, and dilute with ethyl acetate (75 mL). Separate and extract the aqueous portion with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments to give a yellow solid (1.35 g, 40%). ES/MS m/z (35Cl) 334.4 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.O>O1CCCC1>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](Nc2nc3ccccc3o2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl (2S,4R)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [product of Reference Example 4(2), 3.32 g] and triethylamine (1.4 mL) were dissolved in tetrahydrofuran (20 mL). 2-Chlorobenzoxazole (0.86 mL) was added thereto and the mixture was stirred at room temperature for 48 hr. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give methyl (2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (1.48 g) as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[O:15]=[C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]#[CH:19])/[C:10](=[CH:9]/[CH:6]2[CH2:7][CH2:8][N:3]([CH2:20][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=3[C:30]([F:31])([F:32])[F:33])[CH2:4][CH2:5]2)/[S:14]1
Reactant: N#Cc1ccc(C=O)c(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (823 mg) in DMF (12.8 mL) were added 4-formyl-3-(trifluoromethyl)benzonitrile (610 mg) and triethylamine (1.42 mL). The reaction mixture was stirred at room temperature for 1.5 hr, and sodium triacetoxyborohydride (1.62 g) was added. The mixture was further stirred at room temperature for 1 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (618 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C)=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.[C:17]([C:19]1[O:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1)#[N:18].[CH3:27]CN(C(C)C)C(C)C>>[CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:24]([C:22]2[O:23][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[O:25])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1ccc(NC)c(N2CCCCC2)c1
Product: CN(C)c1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 63 %

Procedure:
Using a procedure similar to Example 3, step (d), 4-N,N-dimethyl-2-piperidin-1-yl-benzene-1,4-diamine (89 mg, 0.4 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (236 mg, 1.5 mmol) in the presence of DIEA (0.15 mL, 0.88 mmol) to afford 84.7 mg (63%) of the title compound as a yellow powder. 1H-NMR (CDCl3, 400 MHz): δ 9.50 (br s, 1H), 8.29 (d, 1H, J=8.9 Hz), 7.21-7.24 (m, 2H), 6.58 (d, 1H, J=2.7 Hz), 6.54 (dd, 1H, J=2.8, 9.0 Hz), 2.95 (s, 6H), 2.84-2.87 (m, 4H), 1.78-1.82 (m, 4H), 1.65 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C19H22N4O2, 339.1 (M+H), found 339.1.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=[O:37])[CH:26]([N:34]=[C:35]=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C.O.[OH-].[Li+]>ClCCl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:35]([NH:34][C@H:26]([C:25]([OH:37])=[O:24])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:36])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccccc1)N=C=O
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A mixture of 1-(4-tert-butylbenzyl)-1H-indol-5-amine (0.233 g, 0.84 mmol) and 2-isocyanato-3-phenyl-propionic acid ethyl ester (0.10 g, 0.8 mmol) in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in 2:1:1 THF/MeOH/Water (10 mL). Lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents were removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid. The solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as an off-white solid (0.15 g, 40%): MS (ESI) m/z 470; MS (ESI) m/z 468.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.[CH3:21]N(C=O)C>>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][CH2:14][CH2:21][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1
Reactant: BrCCC1OCCO1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnn(CCCC2OCCO2)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
To an ice-cooled stirred solution of ethyl 1H-pyrazole-4-carboxylate (2.0 g, 14.3 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.68 g, 17.1 mmol). The reaction mixture was allowed to warm to RT over 20 minutes and 2-(2-bromoethyl)-1,3-dioxolane (2.84 g, 15.7 mmol) added. The reaction mixture was heated at 60° C. for 16 hours. The reaction was partitioned between ethyl acetate and brine. The organic phase was washed with further brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (2.14 g, 59%).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.[C:43](=[O:46])([OH:45])[O-].[Na+]>>[C:36]([OH:38])(=[O:37])/[CH:35]=[CH:33]/[C:43]([OH:45])=[O:46].[C:36]([OH:38])(=[O:37])/[CH:35]=[CH:33]/[C:43]([OH:45])=[O:46].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: O=C([O-])O
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O

Procedure:
4.2 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.76 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 190-200° C. for 3.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (100:5:1). The desired fraction was collected, dissolved in 16 ml of ethyl acetate; a solution of 867 mg of fumaric acid in 16 ml of methanol was added, followed by concentration. Acetone was added to the residue; the crystal precipitated was collected by filtration, washed with acetone and dried to yield 2.30 g of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOCCS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Combine allyl hydroxyethyl ether (1.02 g, 10 mmol), and diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain allyl methanesulfonylethyl ether: Rf=0.80 (silica gel, 20% ethyl acetate/dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH:25]1[CH:26]=CC2N(O)N=[N:31][C:29]=2[CH:30]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.N1CCCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([N:31]4[CH2:26][CH2:25][CH2:30][CH2:29]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12)N1CCCC1
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 50 mg, 0.15 mmol) in anhydrous CH2Cl2 (2 mL) was added HOBt (41 mg, 0.31 mmol) followed by EDCI (88 mg, 0.46 mmol). The solution was stirred for 15 minutes, then treated with triethylamine (64 μL, 0.46 mmol) followed by pyrrolidine (38 μL, 0.46 mmol). After stirring at ambient temperature overnight, the reaction mixture was partitioned between saturated NH4Cl (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated. The crude material was purified by silica chromatography (2 to 5% MeOH/CH2Cl2) to yield the final product as white solid (38 mg, 65%). LCMS (apci) m/z=381.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:25][CH2:26][CH3:27])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:7](=[O:9])[CH:8]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:33][C:8]1[C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 4′-[(4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (4.95 g) and sodium acetate (1.25 g) in acetic acid (100 mL) was added bromine (0.78 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (4.3 g, 71%) as a colorless solid.