Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[C:38]([O-:41])(=[O:40])[CH3:39].C(O[Si](CCC[NH+:55]1[CH2:59][CH2:58][N:57]=[CH:56]1)(OCC)OCC)C.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[C:38]([O-:41])(=[O:40])[CH3:39].[NH+:55]1[CH:59]=[CH:58][NH:57][CH:56]=1
Reactant: CCO[Si](CCC[NH+]1C=NCC1)(OCC)OCC
Agent: CC(=O)[O-]
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: c1c[nH+]c[nH]1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.46 g of tetraethoxysilane, 22.06 g of methyltriethoxysilane, 0.55 g of the 30% ethanol solution of triethoxysilylpropyl-4,5-dihydroimidazolium acetate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.13 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-8):
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([CH3:31])=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:32].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([CH3:31])=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:32])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Cc1c2n(c(=O)n(CCCCCl)c1=O)CCCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2n(c(=O)n(CCCCSc3cccc4nccn34)c1=O)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.26 g (6.5 mmol) of 60% oily sodium hydride in 30 ml of N,N-dimethylformamide, 0.98 g (6.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.92 g (6 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.97 g (6.5 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=25/1) to yield 1.61 g (61.8%, white powder) of the desired product.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][C@@H:22]3[CH2:26][CH2:25][N:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:23]3=[O:33])=[C:16]([Cl:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:34][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=2)[CH:19]=[C:18]([Cl:20])[C:17]=1[CH2:21][C@@H:22]1[CH2:26][CH2:25][N:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:23]1=[O:33]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Yield: 98 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(1-morpholin-4-yl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid tert-butyl ester (0.15 g) in dichloromethane (5 mL) with TFA (1 mL) and stir the reaction at room temperature for 12 hours. Remove the solvent and excess TFA in vacuo to afford 0.165 g (98%) of the title compound. MS (m/z): 449 (M+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[O:17][CH2:16][CH2:15][NH:14][CH2:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:14]2[CH2:15][CH2:16][O:17][CH:12]([C:9]3[NH:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13]2)[N:22]=[C:21]([NH2:26])[N:20]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: c1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)n1
Yield: 115.1 %

Procedure:
A solution of 2-(4-phenyl-1H-imidazol-2-yl)morpholine (550 mg, 2.07 mmol), 4,6-dichloro-2-pyrimidinamine (339 mg, 2.07 mmol) and Hunig's base (0.901 mL, 5.17 mmol) in ethanol (80 mL) was heated at 85° C. for 5 hours. The mixture was concentrated to afford the crude title compound (850 mg) as a brown oil. LC-MS (ES) m/z=357 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[NH:5][CH:6]=1.[ClH:14]>>[Cl:14][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[NH:5][CH:6]=1
Reactant: Cl
Reactant: Oc1ccc(-c2nc(Br)c[nH]2)cc1
Product: Oc1ccc(-c2nc(Cl)c[nH]2)cc1
Reaction time: 120 h
Yield: 49 %

Procedure:
Into a glass, thick-walled tube was placed 11 (1.5 g, 0.0063 mol) and 12N HCl (100 ml). The contents were frozen and the tube sealed and placed in a bath at 120° C. After 5 days, the contents in the tube were cooled, filtered, the solid stirred overnight with saturated NaHCO3 solution and filtered to yield 0.59 g (49%) of 13.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:19][C@H:20]([OH:21])[CH3:22])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H]1CO1
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc2ccc(OC[C@@H](C)O)cc2n1
Temperature: 80 °C
Yield: 86.4 %

Procedure:
To a stirred mixture of 2-methylquinolin-7-ol (0.400 g, 2.51 mmol), Cs2CO3 (2.46 g, 7.54 mmol) and DMF (16 mL) was added (R)-2-methyloxirane (0.438 g, 7.54 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1% MeOH in EtOAc) to give (R)-1-(2-methylquinolin-7-yloxy)propan-2-ol (0.471 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[O:3]1.CO>[Pd].C1C=CC=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:2]2([CH3:1])[CH2:11][CH2:10][C:9]3[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=3[CH3:12])[O:3]2)=[CH:19][CH:20]=1
Reactant: Cc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: Cc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2
Yield: 74.3 %

Procedure:
Following a procedure similar to that described in Preparation 4, 760 mg of 2,5,6,7,8-pentamethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 31) were hydrogenated, using 100 mg of 10% w/w palladium-on-carbon, 20 ml of methanol and 70 ml of benzene, at atmospheric pressure, to afford 520 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3](=[O:20])[CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=1.[CH3:23][Mg+].[Br-].O.Cl>C1COCC1.CCOC(C)=O>[OH:20][C:3]([CH3:23])([C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)(C)C(=O)CNc1cc(C(=O)O)nn1-c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(C)(O)CNc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
200 mg (0.664 mmol) 5-(3,3-Dimethyl-2-oxo-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid are dissolved in 10 ml dry THF under argon and cooled to 0° C. in an ice bath. 0.664 mmol (1 eq) of MeMgBr (3.0M solution in Et2O) are added within 5 minutes and the resulting mixture is allowed to reach RT overnight. 20 ml of water and EtOAc are added, then the pH is adjusted to 3-4 by addition of 10% HCl solution and the phases are separated. The organic phase is dried over Na2SO4 and the solvent removed to yield 110 mg (51%) of 5-(2-Hydroxy-2,3,3-trimethyl-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4Cl)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31].CN1CCOCC1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4[NH:28][C@H:29]([CH2:30][OH:31])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(N[C@H](CO)Cc5ccccc5)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a solution of 3-[6-(4-acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-chloro-1 H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (0.78 mg, 5.2 mmol) and N-methyl morpholine (2 mL). The reaction mixture was heated to 80° C. for 12 h, cooled to room temperature and concentrated with high vacuum. The residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (0.90 g, 69%). 1H NMR (400 MHz, CD3OD) δ 7.36 (1H, s), 7.02–7.23 (6H, m), 6.80 (1H, s), 5.98 (1H, d, J=7.5 Hz), 4.10–4.12 (3H, m), 3.67–3.78 (6H, m), 3.06–3.11 (3H, m), 2.90 (1H, dd, J=7.8, 13.6 Hz), 2.54 (3H, s), 2.12 (3H, s). LCMS (M+H)+ m/z 501 (t=1.30 min.).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:29]3[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH:28]=3)[N:7]2[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N3CCOCC3)c3nc(CO)cn23)CC1

Procedure:
Compound 1e was subjected to Suzuki coupling reaction conditions with N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester using the method described in Example 1, Step G to obtain compound 26a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H29N5O4: 416.2 (M+H). Found 416.3.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: COC(=O)c1cccc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: COC(=O)c1cccc(N2CC[C@H](N)[C@H](OC)C2)c1
Yield: 87.5 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (42a) (180 mg) and a 10% palladium-carbon catalyst (150 mg), to obtain 104.5 mg of the title compound as a white solid. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:21]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CNC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.6 %

Procedure:
A solution of 4-methylbenzylamine (2.0 mL, 15.7 mmol), and triethylamine (4.4 mL, 31.6 mmol) in CH2Cl2 (50 mL) was cooled in an ice bath and treated dropwise with 2-methylbenzoyl chloride (2.5 mL, 19.2 mmol). After the end of the addition the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 14 hours the resulting white suspension was diluted with CH2Cl2 (100 mL), and quenched by the addition of water (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with CH2Cl2 (3×30 mL), and the combined organics were dried over Na2SO4, filtered and concentrated to afford a white solid. The crude solid was recrystallized from ethyl acetate/hexane to afford 2-methyl-N-(4-methylbenzyl)benzamide (3.18 g, 85% yield) as a white crystalline solid: 1H-NMR (400 MHz, CDCl3): δ 7.36 (1H, dd, J=7.6, 1.3 Hz), 7.32-7.14 (7H, m), 5.98 (1H, br s), 4.59 (2H, d, J=5.6 Hz), 2.47 (3H, s), 2.35 (3H, s) ppm.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([O:20]C3C=CC=CC=3)=O)=[CH:16][C:11]=2[N:10]=[C:9]1[N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=O)(C)(C)C.C(N(C)C1N(C(OC(C)(C)C)=O)C2C=C(NC(OC3C=CC=CC=3)=O)C=CC=2N=1)(C)C.Cl.[F:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)=[CH:67][CH:66]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[F:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[CH2:72][CH2:73][N:74]([C:18]([NH:17][C:15]3[CH:14]=[CH:13][C:12]4[N:8]=[C:9]([N:27]([CH:29]([CH3:30])[CH3:31])[CH3:28])[NH:10][C:11]=4[CH:16]=3)=[O:20])[CH2:75][CH2:76]2)=[CH:67][CH:66]=1
Reactant: CC(C)N(C)c1nc2cc(NC(=O)Oc3ccccc3)ccc2n1C(=O)OC(C)(C)C
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: CC(C)N(C)c1nc2ccc(NC(=O)Oc3ccccc3)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)N(C)c1nc2ccc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)cc2[nH]1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
To a solution of said mixture (157 mg of tert-butyl-2-[isopropyl(methyl)amino]-5-[(phenoxycarbonyl)amino]-1H-benzimidazole-1-carboxylate and tert-butyl 2-[isopropyl(methyl) amino]-6-[(phenoxycarbonyl)amino]-1H-benzimidazole-1-carboxylate in chloroform (3 ml), 4-(4-fluorophenyl)piperidine hydrochloride (76 mg) and triethylamine (0.16 ml) were added and heated at 60° C. for 1.5 hours. The reaction liquid was cooled and after addition of water, extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure and the resulting residue was purified on preparative TLC (hexane/ethyl acetate=1/9). Thus obtained compound was dissolved in trifluoroacetic acid (2 ml) and stirred for an hour. The reaction liquid was made alkaline by addition of 4N-aqueous NaOH solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure and purified on preparative TLC (methanol/chloroform=1/9) to provide the title compound (11 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]2[CH3:15]>CO.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]2[CH3:15]
Reactant: Cn1c(=O)[nH]c(=O)c2c(N)c([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)[nH]c(=O)c2c(N)c(N)ccc21
Yield: 103.5 %

Procedure:
A suspension of 5-amino-1-methyl-6-nitroquinazolin-2,4-dione (400 mg, 1.64 mmol) in MeOH (70 mL) was hydrogenated over 10% Pd/C (150 mg) in a Parr shaker at 50 psi until uptake ceased. The catalyst was removed by filtration and the filtrate concentrated to yield 5,6-diamino-1-methylquinazolin-2,4-dione (350 mg, 99% crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:17][CH3:18])[C:13]=1[CH2:14][CH2:15][CH3:16])[CH2:6]P(=O)([O-])[O-].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CCCc1c(OC)cc(CP(=O)([O-])[O-])cc1OC
Product: CCCc1c(OC)cc(C=Cc2cc(F)cc(F)c2)cc1OC
Yield: 27 %

Procedure:
This material was prepared from (3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 3,5-difluorobenzaldehyde in 27% yield in the same way as described in Example 21. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.66 (qint., J=7.0 Hz, 1H), 3.90 (s, 6H), 6.72 (s, 2H), 6.8-7.2 (m, 5H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: C1CCCNCC1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCCCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 60 mg; 0.20 mmol) and azepane (0.23 mL; 2.0 mmol) to 250° C. under microwave irradiation according to the procedure described in Example 14 provided after purification by reverse phase HPLC, 5-azepan-1-yl-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (41 mg, 58%) as an off-white powder. ES-HRMS m/e calcd for C21H33N4O (M+H+) 357.2649, found 357.2644.
Reaction SMILES: II.O[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[N:11]=[N:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1>[N:11]1[N:12]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=2[CH3:21])[CH:4]=[C:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: Cc1cc(O)cc(C)c1/N=N/c1ccccc1CO
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-n1cc2ccccc2n1
Reaction time: 0.67 h

Procedure:
Iodine (3980 mg, 15.7 mmol) was added to the orange solution of (E)-4-((2-(hydroxymethyl)phenyl)diazenyl)-3,5-dimethyphenol (2680 mg, 10.46 mmol), triphenylphosphine (4110 mg, 15.7 mmol) and imidazole (2140 mg, 31.4 mmol) in tetrahydrofuran (30 mL) at room temperature. The mixture was stirred for 40 minutes. The solvent was evaporated. The crude was dissolved in EtOAc/MeOH and loaded to the column and purified by ISCO (40 g silica gel, EtOAc/heptane: 0→50%), leading to the desired product as a white/pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.85 (s, 6H) 6.49 (s, 2H) 7.07-7.21 (m, 1H) 7.32-7.42 (m, 1H) 7.75 (d, J=8.58 Hz, 1H) 7.80 (dd, J=8.78, 0.98 Hz, 1H) 7.96 (d, J=0.78 Hz, 1H) 7.99 (s, 1H). LCMS: m/z=239.2 [M+H].
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18](Cl)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>CN1CCCC1=O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[C:13]4=[N:12]3)=[CH:29][CH:30]=2)=[CH:4][CH:3]=[N:2]1
Reactant: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-n3ccnc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 54.5 %

Procedure:
A solution of 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (149 mg, 0.34 mmol) and imidazole (69.5 mg, 1.02 mmol) in dry 1-methyl-2-pyrrolidinone (3 mL) was heated at 100° C. for 18 h. HPLC/MS analysis indicated 90% complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (5 mL×2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with CH2Cl2/EtOAc to obtain pure title compound (87 mg, 55%) as a yellow solid. MS [M+H]+ 470; HPLC retention time=2.59 min; 1HNMR (400 MHz, CDCl3) δ 8.29 (d, 1H, J=0.5 Hz), 8.18 (s, 1H), 7.80-7.85 (m, 2H), 7.78 (s, 1H), 7.49 (d, 2H, J=7.0 Hz), 7.43 (d, 2H, J=7.0 Hz), 7.13-7.15 (m, 3H), 6.94 (m, 1H), 6.53 (d, 1H, J=0.5 Hz), 5.27 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:35]([N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccccc2)CC1
Reaction time: 0.33 h
Yield: 2069 %

Procedure:
2-(4-{4-[5-(2,4-Difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (0.136 g, 0.29 mmol), benzaldehyde (0.034 g, 0.32 mmol) and acetic acid (cat) was dissolved in DCM (20 ml) and the solution was stirred for 20 min. Then NaBH(OAc)3 (0.12 g, 0.58 mmol) was carefully added. The resulting mixture was warmed to r.t and stirred overnight. The solution was then washed with sat NaHCO3, brine, dried and concentrated to afford the title product as yellow oil (0.15 g, 6 mmol). MS m/e=555.4 [M+H]+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1Cl>>[C:1]([O:4][CH2:22][C:21](=[O:23])[CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1cccc(Cl)c1
Yield: 46 %

Procedure:
This crude material was reacted with acetic acid (1.42 mL, 1.49 g, 24.8 mmol) and triethylamine (3.46 mL, 2.51 g, 24.8 mmol), as described above for the synthesis 10 of 3-(3,4-dichlorophenyl)propan-2-one. Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product (1.22 g, 46% yield): 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H) 3.72 (s, 2H) 4.69-4.71 (m, 2H) 7.08-7.11 (m, 1H) 7.21-7.23 (m, 1H) 7.26-7.29 (m, 2H).