Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 1 h

Procedure:
6-Amino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (8.0 g, 0.038 mol) was mixed with sodium nitrite (3.1 g, 0.045 mol) in acetic acid (120 mL). The mixture was stirred at 75° C. for 1 h. The color of the reaction mixture became pink and then purple. The solution was allowed to cool down to room temperature, and water (40 mL) was added. The solid was collected by suction filtration and washed with water (50 mL) to produce the desired product, which was used directly for next step without further purification. LCMS calculated for C9H15N4O2S: (M+H) 243.1. Found 243.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:35]([C:29]2[N:30]([CH3:34])[C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)=[O:36])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Product: Cn1c(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)cc2cc(F)ccc21

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 5-Fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=508.3.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH:15](I)CCCC.O>CN(C)C=O>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10]
Reactant: O=C1NC(=O)C2CC12
Reactant: CCCCC(I)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CC2C(=O)N1CCCCCl
Reaction time: 48 h

Procedure:
Sodium hydride (0.11 g, 60% dispersion in oil) was added to a stirred solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.5 g) and 1-chloro-4-iodooctane (0.98 g) in dry dimethylformamide (50 ml) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 48 hours and water (50 ml) was then added dropwise. The aqueous mixture was extracted with dichloromethane (2×200 ml) and the combined organic extracts were then washed with water (2×400 ml), dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by chromatography on silica (80 g) using 1:1 ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]([OH:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]>O.C1C=CC=CC=1>[CH3:12][C:4]1([CH3:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][CH2:1][O:13]1
Reactant: C=O
Reactant: CC(C)(O)c1ccccc1N
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCNc2ccccc21
Reaction time: 0.08 h
Yield: 58.5 %

Procedure:
An 8.25-ml solution of 37% aqueous formaldehyde (0.099 mol) was added over 5 minutes to a cooled (0° C.) mixture of 10 g (0.066 mol) α,α-dimethyl-2-aminobenzyl alcohol in 50 ml water. The reaction mixture was then diluted with 50 ml benzene and vigorously stirred for 5 minutes. The aqueous layer was separated and extracted with benzene. The benzene layer of the reaction mixture and the benzene extracts were combined, dried over magnesium sulfate and evaporated. The resulting oil was distilled through a short column to give 6.3 g (b.p. 120° -125° C. at 0.1 mm of Hg) of 4,4-dimethyl-1,2-dihydro-4H-3,1-benzoxazine, as a colorless oil. Elemental analysis showed: %C, calc. 73.6, found 68.3: %H, calc. 8.0, found 7.6; %N, calc. 8.6, found 8.6.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:13][C:14]([F:28])([F:27])[C:15]([N:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[O:16]>ClCCl>[F:13][C:14]([F:27])([F:28])[C:15]1[O:16][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[N:7][C:18]([C:23]([F:25])([F:26])[F:24])([C:19]([F:20])([F:22])[F:21])[N:17]=1
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)C1=NC(C(F)(F)F)(C(F)(F)F)N=C(c2cccc(C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
3-Trifluoromethylbenzonitrile (5.8 g, 3.39 mmol) and 2,2,2-trifluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl) ethylidene}acetamide (1.8 g, 6.90 mmol) were dissolved in dichloromethane (3 mL) and stirred in a sealed vial at room temperature for three days. The solvent and excess reagent were distilled off to give a colorless oil that was chromatographed on silica gel using 5 percent ethyl acetate/hexanes as eluent. The desired product was present as an oil (0.92 g, 63 percent yield) in the first eluted fraction. EIMS (m/z): 432 (M+), 413 (M−F), 363 (M-CF3).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1N.N([O-])=O.[Na+].[IH:24].C(=O)(O)[O-].[Na+]>CS(C)=O>[I:24][C:5]1[CH:6]=[C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:19])([F:18])[F:1]
Reactant: I
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(I)c2)CC1
Temperature: 35 °C
Reaction time: 5 h
Yield: 34.5 %

Procedure:
To a solution of 2-trifluoromethoxy-5-(4-methyl-piperazin-1-yl)-phenylamine (5.0 g, 0.018 mol), sodium nitrite (5.1 g, 0.0734 mol) in dimethyl sulfoxide (180 mL) a solution of 57% hydroiodic acid (9.6. mL, 0.0427 mol) in dimethyl sulfoxide were added dropwise at room temperature in 20 minutes. The reaction was stirred for 5 hours at 35° C., then cooled in a ice bath and sodium bicarbonate in small portion was added until basic pH. The aqueous layer was extracted with dichoromethane (3×500 mL), the organic phases washed with 10% solution of sodium bisulphite (2×500 mL) then water (1×300 mL). The organic phase was dried over anhydrous Na2SO4, the solvent evaporated under vacuum to yield the intermediate (2.4 g, 34%) as a orange solid which was used as such in the next step.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:7])=[CH:12]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Succinic anhydride (2.27 g, 22.7 mmol) was added in portions to a hot solution of tryptamine (3.30 g, 20.6 mmol) and potassium acetate (2.23 g, 22.7 mmol) in acetic acid (10 ml). The reaction solution was heated at the boiling point for 3 h and subsequently stirred at RT overnight and the precipitate which had precipitated out was filtered off and washed with acetic acid and EtOH. Yield: 3.00 g (Ind-61, 60%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)c1ccc(C(C)=O)cc1S(N)(=O)=O

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (6.5 g), diethylamine (7.0 ml) and absolute ethanol (200 ml) was heated under reflux for 22 hours. The solution was concentrated to a gum under reduced pressure and partitioned between ethyl acetate (100 ml) and water (120 ml). The organic phase was separated and evaporated to dryness. Trituration of the residue with aqueous isopropanol gave the diethylamine compound as cream crystals, 5.9 g, m.p. 103°-105°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)ccc1F)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Br)ccc1F)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a mixture of 2-(5-bromo-2-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.33 g, 7.9 mmol) and triethylsilane (5 mL) at 25° C. was added trifluoroacetic acid (1 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×20 mL), washed with saturated aqueous sodium bicarbonate solution (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(5-bromo-2-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.76 g, 24%) as a white solid: LC/MS m/e calcd for C20H21BrFNO2 M+: 406.3, observed: 406.3, 408.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:26]([Si:30]([CH3:39])([CH3:38])[O:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]>C(O)CCC>[C:26]([Si:30]([CH3:39])([CH3:38])[O:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:6]2[C:5]([CH2:9][NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)C1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCc1ccc(NCc2cnc(Cl)nc2N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,4-Dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)-amine (200 mg, 0.71 mmol) (from Example 38c supra) was dissolved in hot n-butanol (2 mL) (Aldrich). After cooling to room temperature, triethylamine (0.20 mL, 0.92 mmol) (Allied Signal) and (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine (198 mg, 0.91 mmol) (from Example 9c supra) were successively added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography (20% ethyl acetate in hexanes) to give (±)-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-{2-chloro-5-[(4-ethyl-phenylamino)-methyl]-pyrimidin-4-yl}-amine as a viscous oil. (Yield 272 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([NH:5][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 15.2 g (125 mmole) of 3,5-dimethylaniline in 60 mL of toluene was added 15 g (146 mmole) of acetic anhydride, whereupon the internal temperature rose to 75° C. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in 150 mL of hot ethyl acetate and the solution allowed to stand for 16 hours. The resulting mixture was cooled at 5° C. for 3 hours and the solid collected by filtration to give 18.43 g (90%) of off white crystals.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][O:11][CH2:12][C:6]2=[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=3)=[CH:17][CH:16]=2)[CH:4]=1>C(O)C.CO>[ClH:1].[CH3:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][O:11][CH2:12][C:6]2=[C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:28][N:29]=[N:30][N:31]=3)=[CH:19][CH:20]=2)[CH:4]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCOC2
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2c(n1)CCOC2
Reaction time: 18 h

Procedure:
Concentrated hydrochloric acid (0.75 ml) was added to a solution of 7,8-dihydro-2-methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5H-pyrano[4,3-b]pyridine (A1) (0.94 g) in ethanol (6 ml) and methanol (3 ml). The solution was left to stand for 18 hours, and the precipitated solid collected by filtration, and washed with ether to give 7,8-dihydro-2-methyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5H-pyrano[4,3-b]-pyridine hydrochloride (0.47 g), as a white solid, m.p. 173°-175° C.; NMR (d6 -DMSO): 2.7(s,3H), 3.0(t,2H), 3.95(t,2H), 4.7(s,2H), 5.4(s,2H), 7.2(d,2H), 7.4(d,2H), 7.5-7.75 (complex m,5H); 13C NMR (d6 -DMSO): 71.0 (benzylic CH2); mass spectrum (negative fast atom bombardment (-ve FAB), DMSO/Glycerol (GLY)): 398 (M-H)- ; microanalysis, found: C,62.8; H,4.9; N,15.9; H2O, 0.9%; C23H21N5O2.HCl.0.25H2O requires C,62.7; H,5.1; N,15.9; H2O 1.0%.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:16]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].Cl>C(O)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][O:30][C:17]2[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:18]=2)[CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([CH3:39])[CH:9]=2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 536.1 (M+); Rt: 1.76 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6](OCC)=[O:7])[CH3:2].[CH3:16][NH:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:11]=[N:18][N:17]([CH3:16])[C:6]=1[OH:7])=[O:15])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cnn(C)c1O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 216 g (1 mol) of diethylethoxymethylenemalonate in 216 g of ethanol, there was added 46 g (1 mol) of methylhydrazine at 10° C. Then, at room temperature, the mixture was stirred and further refluxed for one hour, and thereafter the reaction mixture was left to stand. The precipitated crystals were filtered and dried to obtain 148 g of the title compound melting at 134°-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=O)[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 2-[2-(4-fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester, 11, (0.14 g, 0.4 mmol) and morpholine (0.038 mL, 0.43 mmol) in THF at room temperature is added Na(OAc)3BH (0.125 g, 0.6 mmol) and HOAc (0.022 mL, 0.4 mmol). The solution is stirred 12 hours then partitioned between diethyl ether and NaHCO3. The aqueous layer was extracted several times with ether and the organic layers combined, dried, and concentrated in vacuo to a clear oil which was re-dissolved in ether and one equivalent of ethereal HCl is added and a white solid forms. The solid is collected by filtration and 100 mg (60% yield) of the desired product is isolated as the HCl salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:28][CH:29]1[C:35](=[O:36])[NH:34][C:33]2[N:37]=[CH:38][CH:39]=[CH:40][C:32]=2[CH2:31][CH2:30]1>CN(C=O)C>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH2:10][C:11](=[O:13])[NH:28][CH:29]1[C:35](=[O:36])[NH:34][C:33]2[N:37]=[CH:38][CH:39]=[CH:40][C:32]=2[CH2:31][CH2:30]1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2cccnc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)NC1CCc2cccnc2NC1=O)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 49 %

Procedure:
To 68 mg of 3-t-butoxycarbonylamino-3-methylbutanoic acid in 1 mL of DMF was added 60 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The mixture was stirred at 20° C. for 2 h before 50 mg of 7-amino-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one was added and the reaction was stirred an additional 18 h. The DMF was removed in vacuo and the residue was purified by preparative silica gel layer chromatography to yield 52 mg of the product characterized by its NMR and mass spectra.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>CN(C)C=O.O>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([C:32]([F:31])([F:41])[F:42])[CH:34]=3)=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4cccc(C(F)(F)F)c4)cc3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 53 mg (0.17 mmol) of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 3 mL of dimethylformamide (DMF) was added 72 mg (0.22 mmol) of cesium carbonate (Cs2CO3), followed by 0.034 mL (0.22 mmol) of 3-(trifluoromethyl)-benzyl bromide, and the resulting heterogeneous mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate, and the combined organic extracts were concentrated to give a residue which was chromatographed on silica gel (Biotage; DCM) to afford 65 mg (80% yield) of desired 7-cyclohexyl-6-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H NMR; LC-MS—calcd for C27H23F3N4O [M++H]+: 477.18, found: 477.1.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:8]([CH:7]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][C:22]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:6]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(#Cc1ccccc1)CCN1CCC(Cc2ccccc2)CC1
Yield: 37.9 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (200 mg, 0.87 mmol), 4-benzylpiperidine (175 mg, 1.00 mmol) and K2CO3 (368 mg, 2.67 mmol) in CH3CN (10 mL) is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an oil (100 mg, 38%): 1H NMR (CDCl3) 1.45 (m, 2 H), 1.52 (m, 1 H), 1.65 (m, 2 H), 2.05 (t, J=6.6 Hz, 2 H), 2.54 (m, 2 H), 2.68 (m, 4 H), 2.97 (d, J=11 Hz, 2 H), 7.13-7.36 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (10.0114 g; 56.5520 mmoles) and 3,3,3-trifluoro-propionic acid (7.5 mL; 84.9 mmoles) were combined with 6N HCl (20 mL; 120 mmoles) and heated to 108° C. for 18 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (200 mL), then then sodium bicarbonate (15.15 g; 180.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×60 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](OC)=[C:7]([N+:13]([O-:15])=[O:14])[N:6]=1)=[O:4].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([N+:13]([O-:15])=[O:14])[N:6]=1)=[O:4]
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])n1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])n1
Yield: 72.7 %

Procedure:
A solution of 5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester (0.585 g, 2.75 mmol) and cyclohexylamine (0.636 mL, 5.51 mmol) in DMF (8mL) was heated at 70° C. for 20 h. The mixture was poured on brine (50 mL) while mixing vigorously. The solid formed was filtered, washed with water and then dissolved in EtOAc. The solution was washed with water, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-cyclohexylamino-6-nitro-pyridine-2-carboxylic acid methyl ester as a brown oil (0.558 g) which was used in the subsequent step without purification.