Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)Cl)=[CH:5][CH:4]=1.[NH2:21][C:22]([NH2:27])=[N:23][C:24]([NH2:26])=[S:25].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:26]=[C:24]([NH:23][C:22]([NH2:27])=[NH:21])[S:25][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(=S)N=C(N)N
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(NC(=N)N)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (1.00 g) and N-diaminomethylenethiourea (0.65 g) in ethanol (20 ml) was refluxed for 12 hours. After allowing to cool to ambient temperature, then the reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed n alumina, eluting with a mixture of chloroform and methanol. The desired fractions were combined and concentrated in vacuo. The residue was washed with isopropy ether to give 4,5-bis(4methoxyphenyl)-2-guanidinothiazole (0.65 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.BrC[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)[CH2:22][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Reactant: BrCC1CCCCC1
Product: CCCCCCOc1ccc2c(c1)C(=O)OC(C)(C)O2

Procedure:
The title compound was prepared from 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (example 38-a) and (bromomethyl)cyclohexane under conditions analogous to experimental example 38-b, to give the desired product as a white solid. MS: (+) m/z 279.16 (M+1)
Reaction SMILES: C(O[CH2:5][C:6]#[C:7][C@@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>[Pt]=O>[CH2:7]([C@@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH3:5]
Reactant: CC(=O)OCC#C[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Pt]
Product: CCC[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 81 %

Procedure:
420 mg (1 mmol) of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-2-propynyl acetate are hydrogenated in the same manner with platinum oxide and the product is chromatographed over 70 g of silica gel with t-butyl methyl ether/n-hexane (1:1). After 125 ml, there are obtained 300 mg of (3S,4S)-4-propyl-3-tritylamino-2-azetidinone and, after 275 ml, there are obtained 87 mg of 3-[(3S,4S)-2-oxo-3-tritylamino-4-azetidinyl]-propyl acetate.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([NH2:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[BrH:12].BrBr>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:12][CH2:2][C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([NH2:11])=[O:10])[CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cc(C(N)=O)cs1
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1csc(C(=O)CBr)c1

Procedure:
A solution of 5-acetylthiophene-3-carboxamide (0.5 g) in chloroform at 50° was treated with hydrogen bromide in acetic acid (4 drops) and then bromine (0.15 ml) in chloroform (10 ml) dropwise over 30 min. The resulting pale yellow solution was washed with water (2×100 ml), dried and evaporated to small volume to deposit the title compound as a white solid (0.55 g) which recrystallised from water, m.p. 150°-157° (d).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:16]#[N:17])=[O:4].S(=O)(=O)(O)[OH:19].C(=O)(O)[O-].[Na+]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:16](=[O:19])[NH2:17])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CNC(=O)Nc1snc(N2CCCC2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)Nc1snc(N2CCCC2)c1C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 10.5 g of 1-methyl-3-(4-cyano-3-(1-pyrrolidinyl)-5-isothiazolyl)urea and 15 ml of sulfuric acid was heated at 100° during 21/2 hours. The mixture was poured into 250 ml of stirred ice-water and neutralized by slow addition of saturated sodium bicarbonate solution. The separated solid was collected by filtration. The filtrate was allowed to stand for a short time, and filtered again. The collected solid was found to be a mixture of the desired product and unreacted starting material. A third solid that formed when the filtrate was allowed to stand overnight was isolated by filtration to give 4.6 g of 1-methyl-3-(4-carbamoyl-3-(1-pyrrolidinyl)-5-isothiazolyl)urea, which darkened at 241°, then decomposed at 257°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][N:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH2:2][C:3]1=[O:4]
Reactant: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C

Procedure:
The mixture of 2-Chloro-N-methyl-N-(4-nitrophenyl)acetamide (100 mg, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), 2-(di-tert-butylphosphino)biphenyl (13 mg, 0.044 mmol) and triethylamine (91 μl, 0.66 mmol) in toluene was heated at 80° C. for 3 h. The reaction was 78% complete by NMR.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:19][C:2]([F:1])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[C:6]=1[F:17])[OH:4]
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reaction time: 24 h

Procedure:
2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.045 g, 0.16 mmol) was dissolved in ethanol (10 ml) and sodium borohydride (0.026 g, 0.064 mmol) was added. The resulting mixture was stirred for 24 h, after which aqueous sodium carbonate (10%, 20 ml) was added. The aqueous phase was extracted with ethylacetate (3×20 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. Yield: 0.03 g. MS m/z (rel. intensity, 70 eV) 277 (M+, 87), 276 (69), 178 (14), 103 (19), 56 (bp).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([OH:32])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33]([NH:35][NH2:36])=[O:34].CCOC(C)=O>C1COCC1.[Cl-].[Na+]>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:36][NH:35][CH:33]=[O:34])=[O:32])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNC=O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.9 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and exatracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:14]3[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[C:1]1([C:7]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([NH:26][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)c1ccccc1

Procedure:
But starting with 0.3 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole-3ylamine, 0.095 cm3 of triethylamine and 0.088 cm3 of benzoyl chloride in cm3 of dichloromethane. After flash chromatography on a column of silica [eluent: dichloromethane], 0.14 g of N-(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)benzamide is thus obtained in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].BrC(C)COC1C2C(=CC(OC)=CC=2)N=CC=1.Br[CH2:29][CH:30]([O:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1)[CH3:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:31][CH:30]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)[CH3:29])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: COc1ccc2c(OC(C)CBr)ccnc2c1
Agent: COc1ccc2c(OCC(C)Br)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OC(C)Cn3cc(Br)ccc3=O)ccnc2c1
Reaction time: 0.17 h

Procedure:
To a stirring solution of 5-bromo-2(1H)-pyridone (100 mg, 575 μmol) in DMF (1 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 27.6 mg, 1149 μmol) and stirred for 10 min. To this suspension was added 4-(2-bromopropoxy)-7-methoxyquinoline (170 mg, 575 μmol) and 4-(1-bromopropan-2-yloxy)-7-methoxyquinoline (170 mg, 575 μmol) mixture in DMF (1 mL). The mixture was stirred at 40° C. for 48 h. The reaction was quenched with 5% NaHCO3 and extracted with CH2Cl2 (4×10 mL). The combined organics were dried over MgSO4, concentrated to a residue from toluene, and purified on 12 grams of silica eluting with 30-60% of 5% (MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 389/391. Calc'd exact mass for C18H17BrN2O3: 388. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.52 (d, J=6.26 Hz, 3H) 3.90-4.01 (m, 4H) 4.48 (dd, J=13.60, 3.23 Hz, 1H) 5.05-5.14 (m, 1H) 6.45 (d, J=9.59 Hz, 1H) 6.67 (d, J=5.48 Hz, 1H) 7.18 (dd, J=9.19, 2.54 Hz, 1H) 7.24-7.31 (m, 1H) 7.37 (d, J=2.15 Hz, 1H) 7.53 (d, J=2.54 Hz, 1H) 8.01 (d, J=9.19 Hz, 1H) 8.61 (d, J=5.48 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) 8 ppm 17.29, 54.82, 55.55, 71.78, 97.82, 100.08, 107.03, 116.03, 118.81, 121.93, 122.66, 138.56, 143.08, 151.11, 151.41, 160.12, 161.17.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S-:13].[Na+].O>CN(C)C=O>[CH3:12][S:13][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cccc2nc(N)nn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (20 g, 93.9 mmol) in dimethylformamide (60 mL) was added sodium thiomethoxide (8.60 g, 122 mmol) portionwise, and the reaction mixture was stirred at 60° C. for 2 hours. The mixture was allowed to cool, water added (350 mL) and the product collected by filtration to afford the expected compound as a white solid. No further purification was required. Yield: 15.7 g, 93%; LCMS method: 3, RT: 1.38 min, MI: 181 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([I:13])[CH:19]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: Oc1cccc(I)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2cccc(I)c2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1.85 g, 10.9 mmoles), 3-iodophenol (3.6 g, 16.35 mmoles), triphenylphosphine (4.3 g, 16.35 mmoles) in tetrahydrofuran (15 mL) was cooled to 0° C. Diisopropylazodicarboxylate (3.3 g, 16.35 mmoles) was added and the mixture was allowed to warm to room temperature, then stirred for 72 h. The tetrahydrofuran was evaporated and the residue purified by flash chromatography using hexane/ethyl acetate 7:3 v/v as eluent to give compound 106 (2.8 g). This was used directly in step (b).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](N3CC[C@H](O)C3)=[O:35])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:43][O:44][C:45](=[O:50])[C@H:46]([CH2:48][OH:49])[NH2:47]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:47][C@H:46]([C:45]([O:44][CH3:43])=[O:50])[CH2:48][OH:49])=[O:35])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)N3CC[C@H](O)C3)cc2)n1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Product: COC(=O)[C@H](CO)NC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Yield: 62 %

Procedure:
The title compound was prepared in the same manner as described for N-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea, replacing (S)-3-pyrrolidinol with L-serine methyl ester hydrochloride. The desired product was purified by MPLC (EtOAc/hexane/MeOH) and obtained as a solid (150 mg) in 62% yield. A sample of this material was purified further by HPLC and the TFA salt isolated from HPLC was neutralized to provide the title compound. 1H-NMR (DMSO-d6) δ 9.12 (s, 1H), 8.50 (d, J=7.9 Hz, 1H) 8.40 (m, 3H), 7.50-7.38 (m, 6H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (m, 2H), 6.34 (s, 1H), 5.10 (t, J=5.4 Hz, 1H), 4.35 (m, 1H), 3.72 (m, 1H), 3.61 (m, 6H), 1.27 (s, 9H); MS LC-MS [M+H]+=587.2, RT=2.27 min.
Reaction SMILES: [Na].[ClH:2].[CH3:3][O:4][C:5](=[O:10])[C@@H:6]([CH2:8][OH:9])[NH2:7].[C:11]1([CH2:17][CH2:18][CH2:19][CH:20]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([BH3-])#N.[Na+].Cl.CO>CO.C(O)(=O)C>[ClH:2].[CH3:3][O:4][C:5](=[O:10])[C@H:6]([NH:7][CH2:20][CH2:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][OH:9]
Reactant: COC(=O)[C@H](N)CO
Reactant: O=CCCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H](CO)NCCCCc1ccccc1

Procedure:
2% Sodium in methanol (0.052 moles, 59.8 ml) is added to D-Serine methyl ester hydrochloride (0.052 moles, 8.16 g), dissolved in methanol (81.6 ml), to release the base. The formed sodium chloride is precipitated with ethyl ether (163 ml) and filtered off. The filtrate is evaporated to dryness under vacuum. The resulting residue is dissolved in methanol (150 ml), added with 4-phenylbutanal (0.051 moles, 10.69 g) and adjusted to pH 6 with acetic acid, added with sodium cyanoborohydride (0.055 moles, 3.62 g) and reacted at r.t. for 24 hours. The mixture is acidified with methanol HCl, evaporated to dryness under vacuum, taken up in methylene chloride (600 ml) and in a 1M sodium bicarbonate solution. The phases are separated and the aqueous one is extracted again with methylene chloride (3×200 ml), then the combined organic phases are washed with water and evaporated to dryness under vacuum. The product is recovered as the hydrochloride, taking up with ethyl ether (180 ml) and acidifying with ether HCl. The precipitated white solid is dried under vacuum at 30° C. Yield: 5.83 g (40%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[C:15]([C:16]#[N:17])=[CH:14][NH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:3]([C:5]2[N:6]=[C:7]3[C:15]([C:16]#[N:17])=[CH:14][NH:13][N:8]3[C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc2c(C#N)c[nH]n2c(=O)c1O
Agent: NCc1ccc(F)cc1
Solvent: CO
Product: N#Cc1c[nH]n2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 12.9 %

Procedure:
3-Cyano-6-hydroxy-7-oxo-1,7-dihydro-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester (100 mg, 0.427 mmol) was suspended in MeOH (10 mL) and to this was added 4-fluorobenzylamine (122 μL, 1.07 mmol) and the reaction was heated at reflux for 2 days before being cooled to room temperature and filtered. The filtrate was concentrated and recrystalised from hot methanol to afford the product a yellow solid (25 mg, 18%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:37]([O:34][C:31]1[CH:30]=[CH:29][C:28]([C:14]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]3[N:13]=2)=[CH:33][CH:32]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (21 μL, 0.24 mmol) and potassium carbonate (122 mg, 0.88 mmol). The mixture was heated at reflux for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (67 mg, 61%) as a yellow solid. 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.73 (d, 1H), 7.53 (d, 2H), 7.24 (t, 1H), 6.95 (d, 2H), 6.28 (d, 1H), 6.08–5.96 (m, 3H), 5.41 (dd, 1H), 5.27 (dd, 1H), 5.10 (d, 1H), 4.56 (d, 2H), 4.32 (m, 1H), 3.95 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1); Anal. Calcd for C30H34N6O: C, 72.86; H, 6.93; N16.99. Found: C, 72.47; H, 7.05; N, 16.75.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]1([N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[C:18]1([N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:25][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NN(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 6.8 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (500 mg, 2.2 mmol) and N,N-diphenyl-hydrazine (422 mg, 2.2 mmol) in DMF (3 mL) is stirred at 50° C. for 15 min. The mixture is treated with DMTMM (633 mg, 2.2 mmol) and stirred at 50° C. for 3 h. The mixture is diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 75% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid N′,N′-diphenyl-hydrazide (60 mg, 7%). MS: 399 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.30 (d, 1H), 8.15 (m, 1H), 7.61 (m, 1H), 7.44 (m, 1H), 7.35 (m, 4H), 7.22 (m, 4H), 7.04 (m, 2H), 2.64 (s, 3H). IC50=16 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]2C)=[CH:6][C:5]=1[NH:18]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].O.[CH3:25]O>>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH2:12][CH2:13][N:14]([CH3:25])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[NH2:18])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc(N2CCNCC2C)c(F)cc1[N+](=O)[O-]
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Reaction time: 6 h
Yield: 75 %

Procedure:
The acetamide (25.0 g, 0.085 mol) (obtained in step 1 above) was dissolved in methanol (160 mL) and 6 M NaOH solution (42 nL) was added dropwise at ca 30° C. and stirred for 6 h. The mixture was cooled in an ice bath and water (300 mL) was added dropwise. The resultant precipitate was collected by filtration and dried to yield 2-nitro-4-fluoro-5-(4-methylpiperazin-1-yl)aniline (16.0 g, 75%) as a brown solid. mp 154-155° C.; IR (KBr) 3383, 1247 cm-1 ; 1H NMR (CDCl3 ) δ 2.32 (s, 3H, CH3), 2.54 (t, J=5.0 Hz, 4H, N(CH2)2), 3.24 (t, J=4.6 Hz, 4H, N(CH2)2, 6.02 (d, J=7.5 Hz, 1H), 6.12 (brs, 2H, NH2), 7.74 (d, J=14.0 Hz, 1H); Mass (m/z) 254 (M+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][NH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: NCC1(c2ccc(F)cc2)CCCCC1
Yield: 99 %

Procedure:
The title compound was synthesized from 1-(4-fluorophenyl)-cyclohexane-carboxylic acid and ammonia using General Procedure G, followed by General Procedure E in 99% yield as a clear oil. LCMS Rt=6.76 min, m/z=208 (M+1). 1H NMR (CDCl3, δ): 7.24 (ddd, J=3.2, 5.4, 12.2 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 2.67 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79(bs, 2H). 13C NMR (CDCl3, δ, mult): 162.1(0), 159.7(0), 140.3(0), 128.7(1), 128.6(1), 115.1(1), 114.9(1), 54.8(2), 43.2(0), 33.8(2), 26.6(2), 22.1(2).