Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1>CO>[CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:5](=[N:4][C:3]#[N:2])[S:6][CH3:7])[CH2:11]2)[N:9]=1
Reactant: CN=C(N)Nc1nc(C2CCCC(N)C2)cs1
Solvent: CO
Product: CN=C(N)Nc1nc(C2CCCC(NC(=NC#N)SC)C2)cs1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-methylguanidino)-4-(3-aminocyclohexyl)thiazole (0.5 g.) in methanol (15 ml.) was added dimethyl(cyanoimido)dithiocarbonate (0.3 g.) and the resulting solution allowed to stand at room temperature overnight. Concentration of the reaction mixture gave 2-(2-methylguanidino)-4-[3-(3-cyano-2-methylisothioureido)cyclohexyl]thiazole, m.p. 200°-204° (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:38][CH2:37][C:36]5[CH:39]=[CH:40][C:33]([Cl:32])=[CH:34][CH:35]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccc(Cl)cc5)n4)cnc23)CC1
Temperature: 110 °C

Procedure:
A mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol), 4-chloro-benzylamine (0.143 g, 1.0 mmol), Pd2(dba)3 (30 mg), Davephos (40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (12 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 110° C. for 14 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (CH2Cl2:MeOH, 100:1) to give (4-{3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 214 mg, 78%).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:23][CH2:24][C:25](=[O:26])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCBr
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(N2CCC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19455.8 %

Procedure:
10 g of p-tolylhydrazine hydrochloride are dissolved in 100 ml of anhydrous CH2Cl2. The solution is cooled to 0° C. and 19 ml of DBU and then 6.5 mg of 3-bromopropionyl chloride are added. The mixture is stirred at ambient temperature for one hour. The reaction medium is poured onto water, extraction is carried out with CH2Cl2 and then purification is carried out by chromatography on a silica column eluted with an AcOEt/petroleum ether (v/v; 50/50) mixture. 1.3 g of crystals are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36])[C:23]([C:39]([F:41])([F:40])[F:42])=[CH:22][N:21]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C(C)C(N)=O)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Acetic anhydride (15 μL, 0.15 mmol) was added to a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 56 (50 mg, 0.10 mmol) in DCM (5 mL) and pyridine (12 μL, 0.15 mmol) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resultant solid was suspended in water (25 mL) and sonicated for 5 minutes. The solid was collected by filtration and washed with sat. aq. Na2CO3 (20 mL), water (50 mL) then petroleum benzine 40-60° C. to give the title compound 58 as a white solid (42 mg, 77%). LCMS-D: rt 3.176 min; m/z 530.4 [M+H]+.
Reaction SMILES: [NH:1]1[C:8]2=[CH:9][CH:10]=[CH:11][CH2:12][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl.[Br:20]Br>C(Cl)(Cl)Cl.II>[Br:20][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]2[NH:1][C:2]1=[O:13]
Reactant: O=C1CCCCC2CC=CC=C2N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1NC2=CC=CCC2CCCC1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 15 gm (0.084 mol) of hexahydrobenzoazocin-2-one (Chemica Scandinavia, 18, 191 (1964)) in 150 ml of chloroform at 0° C. was added 8.8 gm of PCl5 in small increments over a period of an hour. To this reaction mixture was added 70 mg of iodine, followed by the slow dropwise addition of 84 ml of a 1M solution of bromine in chloroform and this reaction mixture was warmed to room temperature and stirred for 1 hour, at which time it was concentrated at reduced pressure. A mixture of ice and water was added to the crude product and the mixture was extracted three times with methylene chloride. The combined organic fractions were filtered through MgSO4 and concentrated at reduced pressure. The solid bromide was recrystallized with a mixture of chloroform and hexanes to give 12 gm of pure 3-bromohexahydrobenzoazocin-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH:22]2[CH2:25][NH:24][CH2:23]2)=[C:19]([F:28])[CH:18]=1)[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[CH2:14]([O:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH:22]2[CH2:23][N:24]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=3)[CH2:25]2)=[C:19]([F:28])[CH:18]=1)[CH3:15]
Reactant: CCOc1ccc(OC2CNC2)c(F)c1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)(C)O
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(C)=O)cc3)C2)c(F)c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Under an argon atmosphere a mixture of 0.078 g (0.32 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 0.080 g (0.32 mmol) 3-(4-ethoxy-2-fluoro-phenoxy)-azetidine (see US20090286812), 0.26 g (0.081 mmol) Cs2CO3, 0.0036 g (0.016 mmol) palladium(II) acetate, 0.0077 g (0.016 mmol) 2-dicyclohexylphosphine-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (X-Phos) in 1.5 mL toluene and 0.5 mL tert-butanol is stirred for 12 h at 120° C. Few water and methanol is added, the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (GeminiCl8, acetone/water (+0.3% NH4OH)) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15]C(=O)C(C)(C)C)[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[OH-].[Na+]>>[NH2:15][C:10]1[NH:9][C:8](=[O:22])[C:7]2[C:6]3[CH:23]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(N)cc3c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1

Procedure:
N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.065 g, 0.2 mmole) was reacted with aqueous sodium hydroxide in the same manner as in example 2. The product was precipitated from the basic reaction mixture with acetic acid, filtered and washed with water to give 3,9-diaminobenzo[f]quinazolin-1(2H)-one as a tan solid. (0.04 g, 84%) 1H NMR(DMSO-d6, 300 MHz) δ: 5.54(br s, 2H, NH2); 6.35(br s, 2H, NH2); 6.80(dd, J=8.5, 2.3 Hz, 1H, Ar); 6.87(d, J=8.6 Hz, 1H, Ar); 7.52(d, J=8.6 Hz, 1H, Ar); 7.73(d, J=8.6 Hz, 1H, Ar); 8.73(s, 1H, Ar); 10.91(br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)[CH:12]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (4.3 g, 9.4 mmol), 4-trifluoromethylphenylboronic acid (2.6 g, 13.7 mmol), K2CO3 solution (2M, 9.4 mL) and DME (50 mL) was purged with N2 three times before adding Pd(PPh3)4 (400 mg, 0.3 mmol). The mixture was heated to 95° C. for 5 h (followed by HPLC). The reaction was diluted with EtOAc (200 mL) and then was washed successively with NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil. The residue was used crude in the next step.
Reaction SMILES: NC1C=CC(Cl)=CC=1C(C1C=CC(F)=CC=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30]>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:29]([C:28]1[C:27]([F:26])=[CH:35][CH:34]=[CH:33][C:32]=1[F:36])=[O:30]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Product: Cc1ccc(N)c(C(=O)c2c(F)cccc2F)c1
Yield: 16 %

Procedure:
In a manner similar to that described above for compound 1t, p-toluidine and 2,6-difluorobenzoyl chloride were converted to 1aj (16% yield) MS m/z=248 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[N:24]=[C:23]([CH3:25])[O:22][N:21]=4)[CH:15]=3)[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Reactant: Cc1nc(-c2cccc(CBr)c2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nc(-c2cccc(Cn3c(=O)sc4ccc(Cl)cc43)c2)no1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 100 mg (0.54 mmol) of 5-chloro-3H-benzothiazol-2-one, 153 mg (0.59 mmol) of 3-(3-bromomethylphenyl)-5-methyl-1,2,4-oxadiazole and 303 mg (2.16 mmol) of potassium carbonate in 20 ml of acetonitrile are stirred at 80° C. for 1 h. 30 ml of water are added to the reaction mixture, which is then extracted with MTBE, dried and evaporated to dryness. The crude product is purified by column chromatography on silica gel and stirred with ether, giving “A12”: ESI: 358 (M+H); Rt.=3.25 min (method A);
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([CH3:11])([CH3:10])[C:4]#[C:5][Si](C)(C)C.[F-].[K+].CN(C)C=O>CCOCC.O>[CH3:11][C:3]([CH3:10])([CH:2]([OH:1])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4]#[CH:5]
Reactant: CCCCC(O)C(C)(C)C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C#CC(C)(C)C(O)CCCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1 part of (4(RS)-hydroxy-3,3-dimethyl-1-octynyl)trimethylsilane, 1 part of potassium fluoride and 5 parts by volume of dimethylformamide is stirred vigorously at room temperature for about 16 hours, then is diluted with ether and water. The ether layer is separated, washed with water, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford 3,3-dimethyl-1-octyn-4(RS)-ol, which exhibits an infrared absorption maximum at about 3320 reciprocal centimeters.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:32])[CH2:29][CH2:30][OH:31]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:32]=[C:28]([CH2:29][CH2:30][OH:31])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(CCO)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCO)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 112 mg (1.08 mmol) of N′,3-dihydroxypropanimidamide [Graham A. Showell et al., J. Med. Chem., 1991, 34, 1086-1094] were reacted. Yield: 248 mg (66% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cc(Cl)cc([N+](=O)[O-])c1N
Temperature: 28 °C
Yield: 65.4 %

Procedure:
A suspension of 4-chloro-2,6-dinitroaniline (0.261 g, 1.19 mmol, Aldrich, used as received) in 6.66% aq. (NH4)2S (8.0 mL, prepared from 20% aq. solution available from Aldrich) and ethanol (8.0 mL) was refluxed for 45 min during which time it formed dark red solution. It was then cooled to 28° C. and the precipitated solid was filtered and dried under vacuum to yield 146 mg (65%) of pure 5-chloro-3-nitro-1,2-phenylenediamine as a shining red solid, 1H NMR (DMSO-d6): 5.031 (br s, 2H), 6.687 (br s, 2H), 6.912 (d, 1H, J=2.4 Hz), 7.413 (d, 1H, J=2.1 Hz).
Reaction SMILES: O.Cl[C:3]1[C:4]([F:13])=[C:5]([C:8]([F:12])=[C:9](Cl)[CH:10]=1)[C:6]#[N:7].[H][H]>[C].[Pd].C(N(CC)CC)C>[F:12][C:8]1[CH:9]=[CH:10][CH:3]=[C:4]([F:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)c(Cl)cc(Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1F
Reaction time: 7 h
Yield: 95.8 %

Procedure:
To 45 ml of water 15 g of 3,5-dichloro-2,6-difluorobenzonitrile was added and 0.05 g of palladium-carbon catalyst and 17.5 g of triethylamine were added to it. The reaction was carried out in an autoclave at 120° C. for 7 hours while introducing hydrogen gas into it so that the pressure of hydrogen gas in the reaction system was kept at 30 kg/cm2. In the same manner as in the process of the reduction step of Example 1, the reaction mixture was refined to obtain 9.6 g of 2,6-difluorobenzonitrile (yield: 95.8%) and 15.6 g of triethylamine was recovered (recovery rate: 89.1%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:13][C:14](OC(C)=O)=[O:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(O)cc(C=O)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C=O)cc(C(C)C)c1
Yield: 113.8 %

Procedure:
A solution of 33.2 mg (0.202 mmol) of 3-hydroxy-5-isopropylbenzaldehyde and 50 μL (0.53 mmol) of Ac2O in 3 mL of pyridine was stirred at r.t. for 70 min. The solution was concentrated, water and EtOAc were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash silica gel chromatography (20% EtOAc/hexanes) (neutral silica gel) to provide 47.4 mg of 3-formyl-5-isopropylphenyl acetate as a yellow oil with some impurity.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:20][CH2:21][C:22]#[N:23])[C:15]([O:17][CH3:18])=[O:16]>CO>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:20][CH2:21][C:22]#[N:23])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=COCC#N)c1ccccc1OC1CCCCO1
Solvent: CO
Product: COC(=O)C(=COCC#N)c1ccccc1O
Temperature: 20 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of 14.4 g (45.3 mmol) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-cyanomethoxy-acrylate in 50 ml of methanol is admixed with 5 g of acidic ion exchanger and stirred at 20° C. for 3 hours. The ion exchanger is filtered off and the filtrate is concentrated under reduced pressure. The residue is chromatographed over silica gel using dichloromethane/ethyl acetate (10:1). 7.8 g (74% of theory) of methyl 2-(2-hydroxyphenyl)-3-cyanomethoxy-acrylate are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.[OH-].[K+]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(NCCc2cccs2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCCc2cccs2)cc1

Procedure:
A mixture of 29.7 g of ethyl p-[2-(2-thienyl)ethylamino]benzoate and 29 g of potassium hydroxide in 200 ml of 95% ethanol is refluxed for 3 hours. The mixture is worked up as described in Example 4 to give the product, mp 161°-163° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[Ba+2:34].[OH-]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ba:34]
Reactant: [Ba+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: CCO
Product: [Ba]
Temperature: 62.5 °C
Reaction time: 18 h

Procedure:
Raltegravir (100 gm) was suspended in ethanol (600 ml) and then added barium hydroxide (42 gm) at 25 to 30° C. The contents were heated to 60 to 65° C. to obtain a solution. The solution was cooled to 25 to 30° C. and stirred for 18 hours at 25 to 30° C. The solid obtained was collected by filtration and dried to obtain 105 gm of raltegravir barium.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([O:26]CC=C)=[O:25])=[CH:21][CH:22]=3)[C:17]([CH3:30])=[C:16]2[CH3:31])[CH3:14])=[CH:9][CH:8]=1)[CH3:5].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=3)[C:17]([CH3:30])=[C:16]2[CH3:31])[CH3:14])=[CH:11][CH:12]=1)[CH3:5]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O[C@@H](C)C(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.55 g, 1.26 mmol) and morpholine (1.0 mL, 12.6 mmol) in THF (5 mL) was degassed and then Pd(PPh3)4 (0.15 g, 0.13 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH 4. The solvent was removed and the residue was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 396 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CN1CCNCC1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN1CCN(CCCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 22 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 22% yield; NMR Spectrum: 1.95-1.99 (m, 2H), 2.12 (s, 3H), 2.20-2.50 (m, partially hidden by DMSO, 8H), 4.33 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.89 (m, 2H), 8.27 (s, 1H), 8.44 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:10][CH2:9]1
Reactant: Fc1ccc2c(c1)nc(CC(F)(F)F)n2C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc2c(c1)nc(CC(F)(F)F)n2C1CCNCC1
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
11.9 g 1-(1-Benzyl-piperidin-4-yl)-5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzoimidazole×HCl in 200 ml methanol was hydrogenated with 2.5 g Pd/C (10%) as catalyst at 40° C. and 4 bar for 2.5 h. After the reaction the catalyst was removed and the solvent was evaporated. The residue was dissolved in 200 ml water, treated with 4 N NaOH, extracted 2× with ethyl acetate, and the organic layers were extracted 2× with water and dried with MgSO4. Evaporation of the solvent yielded 6.1 g beige crystals (mp. 135° C.).