Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[C:32]1[NH:36][C:35](=[O:37])[O:34][N:33]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23]OS(C)(=O)=O.C(N(C(C)C)CC)(C)C.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>CN(C)C=O>[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][N:54]([CH2:23][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH2:7][O:6][C:5]2[CH:29]=[CH:30][C:31]([C:32]3[NH:36][C:35](=[O:37])[O:34][N:33]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:53][CH2:52]1)(=[O:50])=[O:49]
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCN(S(C)(=O)=O)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
To a solution of 50 mg of methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester in 2 mL of dimethylformamide was added 80 μL of diisopropylethyl amine and 19.2 mg of 1-methylsulfonylpiperazine. The resulting mixture was heated in a sealed tube to 90° C. under microwave irradiation for 5 minutes and then concentrated under reduced pressure. The residue was purified by chromatography on a SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH followed by recrystallization in dichloromethane 9/methanol 1 to give 6.7 mg of 3-{4-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].O>CO>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:23]1[N:24]=[C:20]([CH:17]([CH3:19])[CH3:18])[S:21][CH:22]=1
Reactant: CC(C)c1nc(C=O)cs1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Cl
Temperature: 45 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of 7G (6.4 g, 26.7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (4.8 g, 30.92 mmol, 1.16 eq) and NaOH (4.27 g, 106.8 mmol, 4 eq) in MeOH (200 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The yellow precipitates were collected by filtration and dried to give product 10A (9.96 g, 98.9% yield).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][C:9]1[N:10]=[C:11]([CH2:31][CH2:32][CH3:33])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:13](=[O:15])[CH:14]=1.[Br:34]Br>C(O)(=O)C>[Br:34][C:14]1[C:13](=[O:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:11]([CH2:31][CH2:32][CH3:33])=[N:10][C:9]=1[CH2:8][O:7][CH3:6]
Reactant: CCCc1nc(COC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(COC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of sodium acetate (3.4 g) and 4′-{[4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (15 g) in acetic acid (150 mL) was added bromine (2.1 mL), and the mixture was stirred for 4 hr. Acetic acid was removed in vacuo, and the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (7 g, 39%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)[OH:4].O=[C:21]([CH3:35])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:34][O:33][C:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)[OH:4])[CH3:35])=[CH:29][CH:28]=1)=[O:32]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: CC(C)(C)c1cc(C(O)CN)cc(C(C)(C)C)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Yield: 45 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3 g of 2-amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol (prepared as described in Preparation 35), 2.2 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 100 ml of benzene, 60 ml of absolute methanol and 4 g of sodium cyanoborohydride were used, and that the product was purified by repeated column chromatography through silica gel, using as the eluent first ethyl acetate and then a 1:1 by volume mixture of benzene and ethyl acetate. 2.1 g of 2-[2-(4-methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-di-t-butyl-4hydroxyphenyl)ethanol were obtained. This product was then mixed with 246 mg of fumaric acid, and the mixture was recrystallized from ethyl acetate, to give 1.5 g of the title compound as crystals, melting at 171°-174° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[OH:10])=[CH:5][CH:4]=1)#[CH:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:34](=O)([O:45]C1C=CC([N+]([O-])=O)=CC=1)[O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1>C1COCC1>[C:34](=[O:45])([O:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[O:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=1)[CH:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#Cc1ccc(C(O)C2c3ccccc3-c3ccccc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (4-ethynylphenyl)(9H-fluoren-9-yl)methanol (1.0 equivalent) in THF is added to a 1.0 M solution of LiHMDS (1.0 equivalent) in THF at −78° C. After 15 minutes, a solution of bis(4-nitrophenyl) carbonate (1.5 equivalent) is added. The mixture is allowed to warm slowly to ambient temperature, quenched by addition of 1 N HCl, and extracted with ether. The extract is washed sequentially with 1 N HCl, water, and brine, then dried over mgSO4, filtered, and evaporated. The product 4-nitrophenyl carbonate is purified by chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:40]=[CH:39][C:26]2/[C:27](=[CH:36]/[C:37]#[N:38])/[C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH2:30][CH2:31][C:25]=2[CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:22][C:23]3[CH:40]=[CH:39][C:26]4/[C:27](=[CH:36]/[C:37]#[N:38])/[C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[CH2:30][CH2:31][C:25]=4[CH:24]=3)[C:6]=2[CH:13]=1
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Reactant: CCCc1nc2cc(Br)cc(C)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(C)cc(Br)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
[step 1] Under a nitrogen atmosphere, 6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 300 mg, 1.19 mmol) was dissolved in DMF (3 mL), and the mixture was cooled to 0° C. Potassium carbonate (829 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 20 min. To this mixture was added (E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (421 mg, 1.30 mmol) obtained in Reference Example B1, and the mixture was stirred at room temperature for 4 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/3) to give (E)-[2-(6-bromo-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (615 mg, 95%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([NH2:9])[CH3:8].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1>C1COCC1.C(#N)C>[CH2:7]([NH:9][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]([C:20]([F:23])([F:21])[F:22])[CH:12]=1)[CH3:8]
Reactant: CCN
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCNc1cc(C(F)(F)F)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
K2CO3 (4.15 g, 30.01 mmol), and 2.0 M solution of EtNH2 (15 mL, 30.01 mmol) in THF are added o a solution of 4-chloro-5-nitro-2-trifluoromethyl-pyridine (3.4 g, 15.0 mmol) in acetonitrile (30 mL) under cold conditions . The reaction is complete after stirring at 0° C. for 2 h. Usual work up affords ethyl-(5-nitro-2-trifluoromethyl-pyridin-4-yl)-amine as an yellow-orange viscous oil. 1H NMR (300 MHz, CDCl3): δ 9.24 (s, 1H), 7.09 (s, 1H), 3.45 (t, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][C:30]1([F:41])[O:34][C:33]2[CH:35]=[CH:36][C:37]([CH2:39]O)=[CH:38][C:32]=2[O:31]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:39][C:37]2[CH:36]=[CH:35][C:33]3[O:34][C:30]([F:41])([F:29])[O:31][C:32]=3[CH:38]=2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: O=c1[nH]nc(Br)c(=O)[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc(Br)c(=O)n1Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Yield: 20.4 %

Procedure:
According to Scheme 2 Step 2: A mixture of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione 2(A) (943 mg, 4.91 mmol), CH2Cl2 (40 mL), triphenylphosphine (1.76 g, 6.69 mmol), (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (840 mg, 4.46 mmol) was stirred at 0° C. under nitrogen atmosphere. Di-tertbutyl azodicarboxylate (2.05 g, 8.93 mmol) was added portionwise and the mixture was stirred for 16 hours at room temperature. 200 mL of water were added and the aqueous layer was extracted thrice with 200 mL of DCM. The organic layers were combined and were successively dried over MgSO4, filtered and concentrated under reduce pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column SiO2) using AcOEt/cyclohexane 3/7 as eluant to afford 6-bromo-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione 5(A) (330 mg, 20%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Oc2ccc(F)cc2)cc1
Yield: 140.3 %

Procedure:
To a solution of 6.0 g of 4-fluorophenol (manufactured by TOKYO CHEMICAL INDUSTRIES, LTD.) in 60 ml of chloroform were added 6 ml of triethylamine and a solution of 4.0 g of 4-methoxybenzoyl chloride (manufactured by TOKYO CHEMICAL INDUSTRIES, LTD.) in 40 ml of chloroform, and the mixture was stirred at 55° C for 1 hour. The reaction solution was separated by adding to it 100 ml of dichloromethane, 200 ml of water, and 25 ml of a 1N aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain 8.1 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([CH3:30])[C:22]=2[N:23]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:31]([OH:33])[CH3:32]>>[CH2:31]([O:33][C:28]([C:26]1[CH:25]=[C:24]([CH3:30])[C:22]2[N:23]=[C:19]([C:13]3[C:14](=[O:18])[NH:15][CH:16]=[CH:17][C:12]=3[NH:11][C@H:3]([CH2:2][OH:1])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:20][C:21]=2[CH:27]=1)=[NH:29])[CH3:32]
Reactant: CCO
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Product: CCOC(=N)c1cc(C)c2nc(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of (S)-2-[4-(1-hydroxymethyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile (0.8 g, 2.0 mmol) in ethanol (anhydrous, 80 mL) was bubbled HCl (anhydrous) at 0° C. until saturation. The mixture became a clear solution after a few minutes of bubbling and the solution was stirred at room temperature for 14 h. After concentration in vacuo, the crude product (0.89 g, 100%) was directly used for the next step without purification. LCMS (M+H)+ m/z 446 (t=1.55 min).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][S:5]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:7])=[O:6]
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Step-3: To a stirred solution of 9.84 g (0.049 mol) of 2-trimethylsilanylethanesulfonyl chloride (SESCl) in DCM (100 mL) cooled to −78° C., was added the step-2 product, 4-(piperidin-4-yloxy)benzonitrile hydrochloride, (9.00 g, 0.038 mol). The mixture was stirred 30 min, warmed to −30° C., and stirred 3 h. To this mixture was added 20 mL of 1N NaOH solution added, and the DCM and aqueous layers partitioned. The aqueous layer was back extracted with DCM (50 mL) and the combined organic layers washed with brine (50 mL), saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was repeatedly crystallized from the minimum amount of DCM in hexanes to get the step-3 product, 4-[1-(2-trimethylsilanylethanesulfonyl)piperidin-4-yloxy]benzonitrile, compound B, as a white solid. (12.95 g, 94%): LCMS [MH+] 367, Rt 3.53; 1H NMR (300 MHz, (CD3)2CO-d6) δ 0.80 (s, 9H), 0.97-1.02 (m, 2H), 1.79-1.88 (m, 2H), 2.04-2.15 (m, 2H), 3.28-3.36 (m, 2H), 3.52-3.60 (m, 2H), 4.79 (septet, J=3.9 Hz, 1H), 7.16 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCO)CC2)n1
Yield: 40.2 %

Procedure:
7 g of acetic acid 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propyl ester (18.7 mmol) and 0.67 g of lithium hydroxide (28.0 mmol) were stirred overnight in a mixture of 40 ml of tetrahydrofuran and 40 ml of water. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%) as eluent to yield 2.5 g of the title compound as an oil that crystallized upon standing.
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:9][CH:8]=[C:7]1[OH:24])=O.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>O1CCCC1>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][N:29]=[CH:1][C:3]1[C:16]([OH:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:9][CH:8]=[C:7]1[OH:24]
Reactant: COC(=O)c1ccc(O)c2nc3c(C=O)c(O)c(C)c(O)c3nc12
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c2nc3c(C=NCCN(C)C)c(O)c(C)c(O)c3nc12
Reaction time: 0.33 h

Procedure:
6-Formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylic acid, methyl ester (500 mg, 1.52 mmol) was suspended in 50 ml of tetrahydrofuran and 2-(dimethylamino)ethylamine (160 mg, 1.83 mmol) was added dropwise with stirring to produce a deep purple solution. After about 20 minutes at room temperature, an orange precipitate formed and the reaction mixture gradually developed an orange color.
Reaction SMILES: [CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]4)[CH2:8][CH2:9]2)[CH:22]=1)=[O:32]
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(O)c1ccccc1F
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(NC(=O)c5ccccc5F)c4)CC3)cccc2n1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield according to the general procedure for the preparation of amides (Method C) starting from 3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D21) and 2-fluorobenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][N:14]=[C:13]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:12]=1.NN>[Pd].C(O)C>[NH2:17][C:16]1[C:11]([NH:10][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])=[N:12][C:13]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[N:14][CH:15]=1
Reactant: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)ncc2[N+](=O)[O-])c(C)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)ncc2N)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
4-[[4-[(2,4,6-trimethylphenyl)amino]-5-nitro-2-pyrimidinyl]amino]benzonitrile (0.001 mol), Pd/C 10% (0.025 g), ethanol (20 ml), and hydrazine (0.030 mol) were combined to form a slurry and stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation. The residue was taken up in tetrahydrofuran (20 ml) and methanol (1 ml). A second portion of hydrazine (0.5 g) was added, and the reaction was stirred for 16 hours at room temperature. A third portion of hydrazine (0.5 ml) was added and the reaction was stirred for an additional 16 hours at room temperature. The sample was concentrated by rotary evaporation onto silica gel (1 g) and purified by flash chromatography (eluent: 0.5, 1,2% 10% (NH4OH in CH3OH) in CH2Cl2). The desired fractions were purified by preparatory HPLC to yield 0.24 g of 4-[[5-amino-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (70%); mp. 224-225° C. (comp. 51).
Reaction SMILES: I[C:2]1[NH:3][C:4]([CH2:14][CH2:15][CH3:16])=[C:5]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1>CO>[CH2:14]([C:4]1[NH:3][C:2]([C:2]2[NH:3][C:4]([CH2:14][CH2:15][CH3:16])=[C:5]([C:7]([N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:8])[N:6]=2)=[N:6][C:5]=1[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH2:15][CH3:16]
Reactant: CCCc1[nH]c(I)nc1C(=O)N1CCCC1
Solvent: CO
Product: CCCc1[nH]c(-c2nc(C(=O)N3CCCC3)c(CCC)[nH]2)nc1C(=O)N1CCCC1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
Iodide 6f (0.34 g; 1.0 mmol) was used as starting material. After cooling to rt, the reaction mixture was diluted with CH3OH and filtered. The filtrate was evaporated under vacuum, and the residue was recrystallized from CH3OH to afford 0.080 g (38%) of 1f as yellow prisms. mp>260 C; TLC (EtOAc): Rf=0.14; 1H NMR (DMSO-d6): δ 0.84 (t, 6H), 1.59 (m, 4H), 1.80 (br m, 8H), 2.80 (t, 4H), 3.55 (br m, 4H), 3.90 (br m, 4H); 13C NMR (DMSO-d6): δ 14.3, 23.4, 24.2, 26.9, 31.4, 46.8, 49.0, 132.9, 138.0, 163.7; UV/vis (CH3OH): max (M31 1cm−1)=287 (21200), 294 (20900), 309 (sh); LRMS (CI+): m/z (%): 208 (100), 413 (70) [M+H]+; HRMS (CI+): calcd for C22H33N6O2 413.2665; found 413.2662; Anal. calcd for C22H32N6O20.33(H2O): C, 63.13; H, 7.87; N, 20.08; found: C, 63.21; H, 7.82; N, 20.08.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH2:18][C:19]#[CH:20])[C:8](=[O:21])[C:7]=1[CH3:22])=[O:5])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([CH2:18][C:19]#[CH:20])[C:8](=[O:21])[C:7]=1[CH3:22])([OH:5])=[O:3]
Reactant: C#CCn1c(-c2ccccc2)nc(C(=O)OCC)c(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(C(=O)O)c(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a solution of 1.81 g (6.1 mmol) of 6-ethoxycarbonyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 100 mL of ethanol and 50 mL of THF was added 50 mL of 5% aqueous sodium hydroxide. The mixture was stirred at room temperature for 24 h and rotovapped to remove the bulk of the organic solvents. The residue was diluted with 50 mL of 5% aqueous sodium hydroxide and washed with 100 mL of ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with two 100 mL portions of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of brine, dried over MgSO4 and concentrated to leave 0.87 g (53%) of crude 6-carboxy-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone as a brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH:21][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:13]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(NS(C)(=O)=O)c1ccccc12

Procedure:
A sample of 1'-(1,1-Dimethylethyloxycarbonyl)-3-amino-2,3-dihydrospiro(1H-indene-1,4'-piperidine), prepared by hydrogenation of 500 mg of oxime (1.58 mmole) as in Example 135 Step A, in 3.5 mL methylene chloride containing 475 mg of DMAP (2.46×1.58 mmole), and 550λ of triethylamine (2.51×1.58 mmole), was stirred under nitrogen in an ice bath while adding a solution of 270λ of methanesulfonyl chloride (2.2×1.58 mmole) in 3 mL methylene chloride dropwise over 2-3 minutes. The suspension was stored over night in the refrigerator. It was then washed twice with water, dried with magnesium sulfate and concentrated under reduced pressure to a gum. Preparative TLC on four 8"×8"×1,000 g GF silica gel plates using 1:2 ethyl acetate: hexane afforded the title compound, which crystallized on standing. Yield: 322 mg (54%)