Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a sealed tube was added 2,4-dichloropyrimidine (100 mg, 0.671 mmol), 4-(trifluoromethoxy)phenylboronic acid (138 mg, 0.671 mmol), tetrakis(triphenylphosphine)palladium0) (78 mg, 0.067 mmol), acetonitrile (2 mL) and 2M Na2CO3 in H2O (1.007 mL, 2.014 mmol). Argon was bubbled through the reaction mixture for 1 min. The reaction mixture was then sealed and stirred at 90° C. for 16 hrs. The reaction was cooled to rt and diluted with EtOAc (30 ml). The resulting organic solution was washed with water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex to give the product, 2-chloro-4-(4-(trifluoromethoxy)phenyl)pyrimidine, (62 mg, 0.226 mmol, 33.6% yield) as a white solid. Anal. Calcd. for C11H6ClF3N2O m/z 273.9, found: 275.0 (M+H)+.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccc(Cl)cc1
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 4-chlorophenol:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]#N)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[Mg]Cl.C1C[O:30]CC1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([C:16]([C:11]2[C:10]([CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:30])[CH2:21][CH2:20]1
Reactant: N#Cc1ncccc1CCc1cccc(F)c1
Reactant: CN1CCCCC1[Mg]Cl
Reactant: C1CCOC1
Product: CN1CCC(C(=O)c2ncccc2CCc2cccc(F)c2)CC1
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-(3-fluorophenyl)ethyl]-2-pyridine carbonitrile (28.0 g, 0.123 mole) in 150 mL of dry THF is added 92 mL (1.48 moles/liter, 0.136 mole) of N-methylpiperidyl magnesium chloride over 10 minutes maintaining the temperature at 45-50° C. The reaction is maintained at 40° C. to 50° C. for another 10 minutes and at ambient temperature for 45 minutes. The reaction is quenched to below pH 2 with aqueous hydrochloric acid and the resulting solution is stirred at 25° C. for 1 hour. The pH of the solution is adjusted to about 8, the product is extracted with ethyl acetate, and the solution is concentrated to a residue. Following purification by silica gel chromatography, 38.3 g of product is obtained as a brown oil.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:19]([O-])=[O:20].[Na+]>O>[N:1]1([CH2:7][CH:8]2[CH2:13][N:12]([N:19]=[O:20])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NCC(CN1CCOCC1)O2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CC(CN2CCOCC2)Oc2ccccc21

Procedure:
Similarly 8 g (0.034 mole) of racemic 2-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in about 130 ml. of 2N aqueous hydrochloric acid was treated with 1.3 g (0.019 mole) of sodium nitrite in about 100 ml of water at 0° C. to produce racemic 2-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4]1.[H-].[Na+].[C:16]1([C:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30]Br)[CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CN(C)C=O.C(Cl)Cl.C(C(C)=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[CH3:1][N:2]([CH3:13])[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:30][CH2:29][CH2:28][N:25]1[CH2:24][CH:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]1
Reactant: BrCCCN1CC=C(c2ccccc2)CC1
Reactant: CN(C)C1NC(=O)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 3-dimethylamino-1-isoindolinone (11.7 g) in anhydrous dimethylformamide (300 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (3.5 g) in anhydrous dimethylformamide (150 cc) at a temperature close to 20° C. in the course of 30 minutes, and agitation is continued for 1 hour. Then, a solution of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-bromopropane (20.5 g) in dimethylformamide (150 cc) is added in the course of 15 minutes, and agitation is continued for a further 20 hours. The solution obtained is evaporated to dryness under reduced pressure (1 mm mercury; 0.1 kPa). The residue obtained is dissolved in methylene chloride (350 cc) and washed with distilled water (3×150 cc). The organic extract is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (50 cc) and poured onto silica (1000 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume). The first 2300 cc are eliminated and the eluate corresponding to the next 1500 cc is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in methyl ethyl ketone (80 cc). A solution of oxalic acid (1.9 g) in methyl ethyl ketone (20 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 7.6 g of 3-dimethylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 159° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:27][CH:28]([CH3:32])[CH:29]([NH2:31])[CH3:30].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:31][CH:29]([CH3:30])[CH:28]([CH3:32])[CH3:27])#[N:24]
Reactant: CC(C)C(C)N
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.8 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 3-methyl-2-butylamine (0.88 mmol, 0.101 ml) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 7 h at 75° C. After concentration the residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 4:1) to give the title compound (143 mg, 59%) as white crystals. Mp 134-136° C.; EI SP/MS: 366 (M+); 1H-NMR (CDCl3): δ 0.92 (d, 6H),1.15 (d, 3H), 1.78 (m, 1H), 3.78 (m, 1H), 4.85 (br, 1H), 7.73 (br s, 3H), 8.0 ppm (br, 1H); MA calc for C15H16F6N4 :C, 49.18%; H, 4.40%; N, 15.29%. Found: C, 48.95%; H, 4.38%; N 15.08%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCCOC)=O)=N\C(OCCOC)=O.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[OH:47])[C:42]#[N:43])[CH3:37].[CH2:48]([NH:50][C:51]([C:53]1[CH:54]=[N:55][C:56]([N:59]2[CH2:64][CH2:63][CH2:62][C@H:61](O)[CH2:60]2)=[N:57][CH:58]=1)=[O:52])[CH3:49]>C1COCC1.CCOCC>[C:42]([C:41]1[CH:44]=[CH:45][C:46]([O:47][C@@H:61]2[CH2:62][CH2:63][CH2:64][N:59]([C:56]3[N:57]=[CH:58][C:53]([C:51]([NH:50][CH2:48][CH3:49])=[O:52])=[CH:54][N:55]=3)[CH2:60]2)=[C:39]([O:38][CH2:36][CH3:37])[CH:40]=1)#[N:43]
Reactant: CCNC(=O)c1cnc(N2CCC[C@H](O)C2)nc1
Reactant: CCOc1cc(C#N)ccc1O
Agent: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)c1cnc(N2CCC[C@@H](Oc3ccc(C#N)cc3OCC)C2)nc1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A solution of triphenylphosphine (65 mg, 0.25 mmol) in THF (1 mL) and a solution of bis(2-methoxyethyl) (E)-diazene-1,2-dicarboxylate (56 mg, 0.24 mmol) in THF (1 mL) were added sequentially to a solution of 3-ethoxy-4-hydroxybenzonitrile (26 mg, 0.16 mmol) and (S)—N-ethyl-2-(3-hydroxypiperidin-1-yl)pyrimidine-5-carboxamide (40 mg, 0.16 mmol) in THF (2 mL) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 16 hours. The mixture was diluted with ether (30 mL), and was washed sequentially with aqueous 1N NaOH solution (1 mL) and brine (1 mL). The organic phase was dried over MgSO4, filtered, and concentrated to provide a crude residue, which was purified via preparative HPLC to afford (R)-2-(3-(4-cyano-2-ethoxyphenoxy)piperidin-1-yl)-N-ethylpyrimidine-5-carboxamide. HPLC: Waters XBridge dC18 4.6×50 mm, 5 μm, 95% water/5% acetonitrile linear to 5% water/95% acetonitrile over 4.0 min, 0.03% NH4OH modifier, 2 mL/min; retention time 2.60 min. MS (ES+) 396.1 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].[C:28]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH3:28])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.1 g, 0.3 mmol, see Example 23), and K2CO3 (0.04 g, 0.3 mmol) in 4 mL ACN stirred at room temperature, was treated with MeI (0.06 g, 0.4 mmol), and the resulting mixture was stirred for 12 hours, M+Na=416. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 98 mg of the title compound as a white solid. MS (m/z)=416 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:11])=[O:10].[OH-].[Na+:13]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O-:11])=[O:10].[Na+:13]
Reactant: Cc1ccc(Br)c(S(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Br)c(S(=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
49.6 g of 2-bromo-5-methylbenzenesulfinic acid are dissolved in 400 ml of methanol and treated with an equimolar amount of NaOH in 50 ml of water. The mixture is stirred at RT for 3 hours, the solution is filtered off and the solvents are then removed in vacuo. Finally, residues of water are removed azeotropically using 50 ml of toluene. The solid residue is dried in vacuo over P4O10 and 54.0 g of product are obtained, mp 288-290° C. (with decomposition).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])(=[O:4])=[O:3].[CH:33]1([C:39]23[CH2:46][CH2:45][N:42]([CH2:43][CH2:44]2)[CH2:41][CH2:40]3)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(#N)C>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:33]1([C:39]23[CH2:46][CH2:45][N+:42]([CH2:6][CH2:7][CH:8]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH2:9][N:10]4[CH:14]=[CH:13][N:12]=[C:11]4[C:15](=[O:24])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])([CH2:41][CH2:40]2)[CH2:43][CH2:44]3)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: C1CCC(C23CCN(CC2)CC3)CC1
Reactant: COc1ccccc1C(=O)c1nccn1CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: COc1ccccc1C(=O)c1nccn1CC(CC[N+]12CCC(C3CCCCC3)(CC1)CC2)c1ccc(Cl)c(Cl)c1
Product: CS(=O)(=O)[O-]
Yield: 84.2 %

Procedure:
1-Methanesulphonyloxy-3-(3,4-dichlorophenyl)-4-[2-(2-methoxybenzoyl)imidazol-1-yl]butane (0.59 g) (see Preparation 84) and 4-cyclohexylquinuclidine (0.27 g) (see Preparation 1) were dissolved in acetonitrile (8 ml) and heated under reflux for 3.5 hours. The solvent was removed under reduced pressure and the resulting residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluting with a solvent gradient of 95:5 changing to 85:15, by volume, dichloromethane:methanol to give 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[2-(2-methoxybenzoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate (0.69 g) as a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10](=[CH:15][CH3:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:31]1([C:34]([CH:36](Br)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[CH:31]1([C:34]([CH:36]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[C:10](=[CH:15][CH3:16])[CH2:9]2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[O:35])[CH2:33][CH2:32]1
Reactant: CC=C1CN(C(=O)OC(C)(C)C)CCC1O
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C1CN(C(C(=O)C2CC2)c2ccccc2F)CCC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In 20 ml of methylene chloride, 1.51 g (6.7 mmol) of 1-(t-butoxycarbonyl)-3-ethylidene-4-hydroxypiperidine were dissolved. To the resulting solution, 5 ml of trifluoroacetic acid were added under ice cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture, 11 ml of triethylamine and 1.70 g (6.7 mmol) of α-cyclopropylcarbonyl-2-fluorobenzylbromide were added under ice cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the solid so precipitated was filtered off. The filtrate was then concentrated by evaporation under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: chloroform/methanol=100/1), whereby 1.52 g (yield: 74.9%) of the title compound were obtained as a yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31]Br)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl>C(O)C.[OH-].[Na+].O>[CH:20]1[C:21]2[CH:22]([CH2:24][O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[O:27])[C:23]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCCCSc1ccccc1C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of thiosalicylic acid (500 mg) in ethanol (15 ml) and 2N sodium hydroxide aqueous solution (3.2 ml) was added 3-(9-fluorenylmethoxycarbonylamino)-propyl bromide at ambient temperature and the suspension was stirred for 2 hours. The resulting clear solution was diluted with water (20 ml) and acidified with 1N hydrochloric acid (6.5 ml). White crystals were collected by filtration and the solid was washed with ethanol-water (1:3, 15 ml) and then with n-hexane - diethyl and either (2:1, 15 ml) to give 2-[3-(9-fluorenylmethoxycarbonylamino)-propylthio]benzoic acid (1.07 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[C:5]([F:22])=[C:4]([F:23])[N:3]=1.[Cl:24]CCCl>>[ClH:24].[F:23][C:4]1[C:5]([F:22])=[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:7]([F:8])=[C:2]([F:1])[N:3]=1
Reactant: ClCCCl
Reactant: Fc1nc(F)c(F)c(N2CCN(Cc3ccccc3)CC2)c1F
Product: Cl
Product: Fc1nc(F)c(F)c(N2CCNCC2)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice bath cooled, stirred solution of 1-(2,3,5,6-tetrafluoropyridin-4-yl)-4-benzylpiperazine (Method 20; 4.59 g, 14.1 mmol) in 1,2-dichloroethane (40 ml) was added chloroethyl chloroforinate (1.6 ml, 14.7 mmol) over five minutes. The solution was heated to reflux and stirred for two hours and allowed to cool to ambient temperature. Volatile material was removed by evaporation. The residue was dissolved in methanol, heated to refiux and stirred for 2.5 hours, allowed to cool to ambient temperature. Volatile material was removed by evaporation. The residue was purified by chromatography eluting with 5-10% MeOH in DCM to give a solid which was triturated with ether to give the title compound (2.57 g) as a solid. NMR 3.05 (m, 4H), 3.53 (m, 4H); m/z 236.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:18]12([CH2:28]S(O)(=O)=O)C(C)(C)C(CC1)C[C:19]2=[O:20].[CH:33](=O)CC>>[F:1][C:2]1[C:3]([NH:17][CH:19]([O:20][CH3:33])[CH2:18][CH3:28])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CCC=O
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Product: CCC(Nc1nc(OCc2ccc(F)cc2)ncc1F)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
To a solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.42 mmol) in propionaldehyde (2 mL) was added a catalytic amount of camphorsulfonic acid. The mixture was agitated on an orbital shaker at room temperature for 4 h and then evaporated to dryness. Methanol (2 mL) was added, and the resulting solution was warmed to 60° C. for 1 h. After evaporation, the crude product was purified by reverse phase chromatography to yield the title compound (0.030 g, 24% yield) as a clear, colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.47-7.41 (m, 2H), 7.09-7.01 (m, 2H), 5.41 (dt, J=9.9 and 6.0 Hz, 1H), 5.30 (s, 2H), 5.2 (bd, J˜10 Hz, 1H), 3.12 (s, 3H), 1.88-1.60 (m, 2H), 0.98 (t, J=7.1 Hz, 3H). HPLC-MS 308 (ES−), 310 (ES+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][NH:7][N:6]=1)=[O:4].N#N.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: COC(=O)c1n[nH]cc1N
Yield: 98.9 %

Procedure:
A 2O L, reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10% wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel, a slurry of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 1O vol) was warmed to 30 to 35° C. to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 3O° C. until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9% th).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH3:20][C:21]([CH3:26])=[CH:22][C:23](=O)[CH3:24]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]3[N:1]=[C:23]([CH3:24])[CH2:22][C:21]([CH3:26])([CH3:20])[N:6]3[N:5]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)C=C(C)C
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Product: CC1=Nc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2C(C)(C)C1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and 4-methyl-3-penten-2-one (5 ml) was refluxed for 5 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethyl acetate and hexane to give 6,7-dihydro-2-(4-fluorophenyl)-3-(pyridin-4-yl)-5,7,7-trimethylpyrazolo[1,5-a]pyrimidine (83 mg).
Reaction SMILES: C(N(CC)CC)C.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([OH:38])=O.[NH2:39][C:40]1[N:45]=[C:44]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=2[F:54])[N:43]=[C:42]([C:55](=[N:57]O)[NH2:56])[N:41]=1>CN(C=O)C>[Cl:53][C:49]1[C:48]([F:54])=[C:47]([NH:46][C:44]2[N:45]=[C:40]([NH2:39])[N:41]=[C:42]([C:55]3[N:56]=[C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[O:38][N:57]=3)[N:43]=2)[CH:52]=[CH:51][CH:50]=1
Reactant: O=C(O)c1ccccn1
Reactant: NC(=NO)c1nc(N)nc(Nc2cccc(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(Nc2cccc(Cl)c2F)nc(-c2noc(-c3ccccn3)n2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
Triethylamine (1.10 mL, 7.58 mmol) and 1H-benzotriazol-1-ol (0.77 g, 5.05 mmol) were added to a solution of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.97 g, 5.05 mmol) in DMF (10 mL) and the mixture was stirred for 20 min at room temperature. Picolinic acid (0.62 g, 5.05 mmol) was added and the mixture was stirred for 30 min at room temperature. 4-Amino-6-[(3-chloro-2-fluorophenyl)amino]-N′-hydroxy-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 73, 1.50 g, 5.05 mmol) was added and the mixture was stirred at room temperature overnight before being heated to 85 C for approximately 24 h. The crude compound was purified over Ambersep resin but the impurities remained. The residue was then successively washed with EtOAc, acetone and MeOH and finally hot MeOH to afford the title compound (330 mg, 17%).