Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][OH:13].CC(O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O)=O.C1C=CC=CC=1>C(O)CO>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH:12]=[O:13]
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1C#N
Agent: CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O
Solvent: OCCO
Solvent: c1ccccc1
Product: Cn1c(C=O)nc([N+](=O)[O-])c1C#N

Procedure:
0.91 G. (0.05 moles) of 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole and 2.66 g. of leadtetraacetate are combined in 35 ml. of benzene and refluxed for 12 hours. 0.3 G. of ethylene glycol is added to the reaction mixture to consume excess leadtetraacetate and the reaction mixture is filtered. The benzene solution is washed with water and sodium bicarbonate solution, dried and evaporated to dryness. The residue is recrystallized from isopropanol affording 1-methyl-2-formyl-4-nitro-5-cyanoimidazole, m.p. 130° to 133C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-c5nnn[nH]5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting sequentially with dichloromethane/methanol/concentrated ammonium hydroxide) 95/5/0.1 dichloromethane/methanol/concentrated ammonium hydroxide) 80/20/0.2, the title compound: Rf=0.81 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide) 90/10/0.1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:34]1([CH2:37][NH:38][C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)=[O:49])=[CH:44][CH:43]=2)=[O:40])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:34]1([CH2:37][NH:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]([N:50]3[CH2:55][CH2:54][N:53]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:5])([F:6])[F:7])[C:2]([F:21])([F:20])[F:1])=[CH:10][C:11]=4[CH2:17][CH2:18][CH3:19])[CH2:52][CH2:51]3)=[O:49])=[CH:46][CH:47]=2)=[O:40])[CH2:35][CH2:36]1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CN1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(hydroxymethyl)-3-propylphenyl)propan-2-ol (0.509 mmol, 161 mg) was dissolved in dichloromethane (4 mL) and triethylamine (1.527 mmol, 155 mg) was added. The mixture was cooled to 0° C. before the addition of methanesulfonyl chloride (0.611 mmol, 70.0 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.510 mmol, 154 mg) was added followed by potassium carbonate (1.529 mmol, 211 mg). The mixture was heated to reflux for 16 hours. The mixture was cooled, diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column chromatography to afford the title compound (63 mg). MS (ESI) m/z 601.3 [M+H]+
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+]>O.S(=O)(=O)(O)O>[C:7]([OH:9])(=[O:8])[C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[OH:11]
Reactant: O=N[O-]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
400 g of D-leucine was dissolved in 5 l of water containing 296 ml of concentrated sulfuric acid and cooled to -2°. A solution of 421 g of sodium nitrite in 1.25 l of water was added slowly while holding the temperature at -2°. The mixture was stirred at 0° for 1.5 hours and then allowed to warm to room temperature overnight. The mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 168 g of D-leucic acid as a pale yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:23])[CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(#N)C>[Pd].C(O)C>[N:14]1([C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:23])[CH:22]=2)[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(=O)[nH]cn2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC#N
Product: O=c1cc(N2CCNCC2)nc[nH]1
Reaction time: 6 h
Yield: 63.7 %

Procedure:
A mixture of 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl)-piperazine-1-carboxylic acid benzyl ester (Intermediate 3; 2.00 g, 7.14 mmol) and a catalytic amount of 10% palladium on carbon in ethanol (300 mL) was hydrogenated at atmospheric temperature and pressure. The starting material is not readily soluble in ethanol so it is clearly visible. After 6 h, the amount of starting material was significantly reduced. Hydrogenation was continued overnight, and a large amount of solid was present. Acetonitrile (300 mL) was added and the mixture was heated to dissolve the solid. The catalyst was filtered off using Celite, and the solvent was evaporated from the filtrate to give 6-piperazin-1-yl-3H-pyrimidin-4-one (820 mg, 64%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[Cl:22][C:5]1[C:6]([C:18]([F:20])([F:21])[F:19])=[N:7][N:8]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Intermediate 13 (1 g, 3.36 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.54 g, 4.0 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) afforded the title compound (0.802 mg). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.39 (d, J 9, 2H), 7.82 (d, J 9, 2H), 1.91-1.80 (m, 1H), 1.10-1.00 (m, 2H), 0.80-0.72 (m, 2H).
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[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[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[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:24][CH2:25][CH2:26][C:27]=34)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3CCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,3-dihydro-benzo furan-4-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=479.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1C#N.[CH3:11][Mg]Br.[C:14]([O-:17])([O-])=O.[Na+].[Na+]>C(OCC)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:14](=[O:17])[CH3:11]
Reactant: C[Mg]Br
Reactant: N#Cc1c(N)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1c(N)cccc1Cl
Yield: 67 %

Procedure:
A suspension of 2-amino-6-chlorobenzonitrile (3.67 g, 24 mmol) in diethyl ether (60 ml) was added slowly to methylmagnesium bromide (56 ml, 3 M in Et2O, 170 mmol), and the mixture was heated to reflux, until all starting material was consumed (3 h, HPLC control). The mixture was then placed in an ice bath, and HCl (6M, 58 ml) was slowly added (vigorous reaction). The mixture was then again heated to reflux, cooled and made alkaline by addition of solid Na2CO3. The mixture was extracted several times with ethyl acetate, the combined organic phases were dried (Na2SO4), and the solvent was evaporated under reduced pressure. Purification of the residue by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=100/0−60/40) gave the title compound (2.72 g, 67%). 1H NMR (CDCl3): δ 2.65 (3H, s), 4.91 (2H, bs), 6.58 (1H, d), 6.73 (1H, d), 7.07 (1H, t).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([O:25]C)=[N:23][C:22]3[C:17]2=[N:18][C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:20][C:21]=3[NH2:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[NH2:27][C:21]1[N:20]=[C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:18]=[C:17]2[C:22]=1[NH:23][C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:6][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:9][CH2:10]1
Reactant: BrCc1ccccc1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(Cc4ccccc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.4 %

Procedure:
To the compound (0.26 g, 0.58 mmol) obtained in Step (i) was added trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 20 minutes. Trifluoroacetic acid was evaporated with an evaporator, and to the resultant were added THF (10 ml), benzyl bromide (0.21 ml, 1.74 mmol) and ethyl diisopropylamine (0.75 ml, 4.35 mmol), and the mixture was stirred at room temperature for 15 hours, then stirred at 50° C. for one hour. The resultant was concentrated by an evaporator, and water was added to the residue. The mixture was extracted three times with chloroform, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column (chloroform/methanol=100/1 to 20/1). Then, methanol (1 ml) and a 4N hydrochloric acid in dioxane (1 ml) were added thereto, and the mixture was stirred at room temperature for one hour. The mixture was cooled to 0° C., and neutralized with 4% aqueous ammonia. The precipitated solid was collected by filtration, and washed with water to give the title compound (55 mg, 0.13 mmol) as a white solid. Yield: 22%.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH:9](OCC)(OCC)OCC.[NH2:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.C([O-])(=O)C.[Na+].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH2:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH:20]1[NH:19][C:7]1[C:6]2[CH:5]=[CH:4][O:3][C:2]=2[N:1]=[CH:9][N:8]=1
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1ccoc1N
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC(Nc1ncnc3occc13)C2
Temperature: 130 °C
Yield: 7.2 %

Procedure:
A mixture of 2-amino-3-cyanofuran (270 mg, 2.5 mmol), triethyl orthoformate (1.5 ml, 9.0 mmol), and acetic anhydride (0.18 ml, 1.9 μmol) was heated to reflux at 130° C. for 2 hours. The reaction mixture was cooled, and 2-aminoindan (670 mg, 5.0 mmol), sodium acetate (640 mg, 7.8 mmol), and acetic acid (1.1 ml, 19 mmol) were added, which was further heated to reflux at 130° C. for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (44 mg, 0.18 mmol) having the following physical properties:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1.FC(F)(F)C(O)=O.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>CS(C)=O>[C:41]([C:40]1[CH:43]=[CH:44][C:37]([NH:36][CH2:35][CH2:34][NH:33][C:2]2[N:7]3[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:3]=2)=[N:38][CH:39]=1)#[N:42]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(Cl)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(NCCNc3ccc(C#N)cn3)n2n1

Procedure:
200 mg (0.52 mmol) of ethyl 5-chloro-7-(4-trifluoromethylphenyl)[1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate (Example 149A) and 123 mg (0.62 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (Example 13A) are introduced into DMSO (2 ml), 0.54 ml (3.1 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 90° C. for 30 min. The reaction mixture is purified by preparative HPLC. 98 mg (38% of theory) of the product are obtained as a solid.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:50][CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>C(Cl)Cl.CO>[N:52]1([CH2:51][CH2:50][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Reactant: ClCCN1CCCC1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1cc(OCCN2CCCC2)ccc1Nc1ncc(-c2ccsc2)s1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using 1-(2-chloroethyl)-pyrrolidine hydrochloride. The title compound: ES-MS: 439.9 [M+H]+; single peak at tR=3.36 min (System 2); Rf=0.22 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:47])[C:32](=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].O>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:47])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.75 g of fluorene (10.5 mmol) was dissolved in 40 ml of dehydrated diethylether in a nitrogen atmosphere. To the solution, 7.0 ml of an n-butyl lithium/hexane solution (1.58M: 11.1 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. The solvent was distilled off under reduced pressure and thereby a reddish orange solid was obtained. In a glove box, to the reddish-orange solid, 3.17 g of 3-tert-butyl-1-methyl-6,6-diphenylfulvene (10.6 mmol) was added and dissolved in 50 ml of dehydrated diethyl ether. The solution was stirred for 120 hr while intermittent refluxing in a 50° C. oil bath and stirred at room temperature for 496 hr. To the resulting reaction mixture, 50 ml of a distilled water was gradually added dropwise in an ice bath and diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with distilled waster and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give red oil. The red oil was re-crystallized from ethanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 0.648 g (1.39 mmol) as a pale yellow solid (yield: 13%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH3:36])[CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O.CO.O1CCCC1>[CH2:7]([S:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[CH3:36])[CH:20]=1)=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCCSCCc1cnn(CCCCC2c3ccc(O)cc3CCC2(C)c2ccc(O)cc2)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCS(=O)CCc1cnn(CCCCC2c3ccc(O)cc3CCC2(C)c2ccc(O)cc2)c1
Reaction time: 16 h

Procedure:
A solution of sodium metaperiodate (0.1 g.) in water (2 ml.) was added to a stirred solution of (1RS,2RS)-1-{4-[4-(2-hexylthioethyl)pyrazol-1-yl]butyl}-1,2,3,4-tetrahydro-2-p-hydroxyphenyl-2-methylnaphth-6-ol (Example 1; 0.23 g.) in a mixture of methanol (4 ml.) and tetrahydrofuran (4 ml.) and the mixture was stirred at laboratory temperature for 16 hours, diluted with water (20 ml.) and extracted three times with methylene chloride (10 ml. each time). The combined extracts were dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 49:1 v/v mixture of ethyl acetate and ethanol as eluent. There was thus obtained as an oil (1RS,2RS)-1-{4-[4-(2-hexylsulphinylethyl)pyrazol-1-yl]butyl}-1,2,3,4-tetrahydro-2-p-hydroxyphenyl-2-methylnaphth-6-ol.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)oc2c1
Reactant: CCOC(=O)CCNC
Product: COc1ccc2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)oc2c1

Procedure:
Using 4-{[cyclohexyl(6-methoxy-1-benzofuran-2-yl)methyl]amino}benzoic acid (300 mg) synthesized above and ethyl 3-(methylamino)propanoate (125 mg) and in the same manner as in Example A1(4), the title object compound (201 mg, 55%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:40])[C:20]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([CH:29]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:40])[C:20]=2[N:21]2[CH2:22][CH2:23][N:24]([C:27]([CH:29]3[CH2:30][NH:31][CH2:32]3)=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCN(C(=O)C2CNC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 3-(4-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (73 mg, 0.1309 mmol) (prepared using a procedure similar to Example 8) was dissolved in DCM (219.0 μL). TFA (298.5 mg, 201.7 μL, 2.618 mmol) was added and the mixture was stirred at RT for 2 hr. The reaction mixture was concentrated in vacuo and the residue was purified by fractionlynx yielding 2-amino-N-(4-(4-(azetidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide as a cream solid. MS (ES+) 458.1.
Reaction SMILES: S(C1C=CC(N2[C:15](=[O:16])[CH:14]=C(C)N2)=CC=1)(O)(=O)=O.S(C1C=C(N2C(=O)C=C(C)N2)C=CC=1)(O)(=O)=[O:19].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[N:46]1[C:50](=[O:51])[CH:49]=[C:48]([CH3:52])[NH:47]1.ClC1C=C(S(O)(=O)=O)C(Cl)=CC=1N1C(=O)C=C(C)N1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[N:46]1[C:50](=[O:51])[CH:49]=[C:48]([C:52]([O:16][CH2:15][CH3:14])=[O:19])[NH:47]1
Reactant: Cc1cc(=O)n(-c2cccc(S(=O)(=O)O)c2)[nH]1
Reactant: Cc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)[nH]1
Reactant: Cc1cc(=O)n(-c2cc(S(=O)(=O)O)ccc2Cl)[nH]1
Agent: Cc1cc(=O)n(-c2cc(Cl)c(S(=O)(=O)O)cc2Cl)[nH]1
Product: CCOC(=O)c1cc(=O)n(-c2cc(S(=O)(=O)O)ccc2Cl)[nH]1

Procedure:
and for economic reasons and performance properties, the preferred pyrazolones are: 1-(4'-sulfophenyl)-3-methyl-5-pyrazolone; 1-(3'-sulfophenyl)-3-methyl-5-pyrazolone; 1-(2'-chloro-5'-sulfophenyl)-3-methyl-5-pyrazolone; and 1-(2',5'-dichloro-4'-sulfophenyl)-3-methyl-5-pyrazolone.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.B.C1COCC1>C1COCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A suspension of 4-bromomethylbenzoic acid (5.04; 23.3 mmol) in THF (30 ml) was cooled to 0° C. and treated with borane/THF (35 mmol). The ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The excess borane was quenched with MeOH, and then with water, and the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 4% HCl, water NaHCO3, brine, dried (MgSO4), filtered, concentrated in vacuo to afford 4.44 g (94%) of the title compound.