Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10]3[C:15]([C:16]4([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[N:23]#CBr>C(Cl)Cl>[C:22]([N:19]1[CH2:20][CH2:21][C:16]2([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[CH2:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]1)#[N:23]
Reactant: N#CBr
Reactant: COc1cccc2c1Cc1ccccc1C21CCN(C)CC1
Solvent: ClCCl
Product: COc1cccc2c1Cc1ccccc1C21CCN(C#N)CC1

Procedure:
4-Methoxy-1'-methyl-9,10-dihydroanthracene-9-spiro-4'-piperidine (12.6 g.) and cyanogen bromide (5.6 g.) in methylene chloride (250 ml.) are stirred at room temperature for 18 hours. The reaction mixture is evaporated to dryness, and the residue is taken up in chloroform, the solution washed with water and with brine, dried (MgSO4), and evaporated to give a brown oil which is chromatographed rapidly on silica gel. Elution with ethyl acetate affords pure 1'-cyano-4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine as an oil, characterised by the peak at 2200 cm-1 (C≡N stretching) in its infra-red spectrum.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH:11](O)=O.C([O-])(O)=O.[Na+]>Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:11][NH:10][C:5]=2[CH:4]=1
Reactant: CSc1ccc(N)c(N)c1
Reactant: O=CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-(Methylthio)benzene-1,2-diamine (10.7 g, 69.2 mmol) was dissolved in 230 mL of aqueous 4N HCl with stirring. Formic acid (7.85 mL, 208 mmol) was added and the reaction was refluxed for 1 h. The reaction was cooled to rt then concentrated in vacuo to a dark solid. The dark solid was dissolved In 500 mL of MeOH with stirring, NaHCO3 (51.0 g, 607 mmol) was added and the reaction was stirred for 1 h. The reaction was then filtered, and the filtrate concentrated in vacuo to a solid. The solid was stirred in 400 mL of EtOAc and heated to reflux, then filtered. The filtrate was concentrated in vacuo to a solid. The solid dissolved in 400 mL of DCM with stirring, then dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give 11.3 g (99%) of the crude 6-(methylthio)-1H-benzimidazole as a dark oil. 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.52 (m, 2H), 7.24 (m, 1H), 2.50 (s, 3H). MS m/z 165 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>C1(C)C=CC=CC=1.CC(C)=O>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C=NCCCl
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCn1c(C#Cc2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 100 °C
Yield: 54.2 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is suspended in toluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) is added, and the mixture is heated at 100° C. for 5 h. The reaction mixture is then cooled, diluted in acetone, and absorbed onto silica. Purification by column chromatography (5-10% EtOAc in CH2Cl2) yields 1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (73 mg, 54%) as a yellow solid.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:15]=[CH2:16])[CH:3]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:21][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:15]=[CH2:16])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C=Cc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Product: C=Cc1cc(NC(C)(C)C)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 10.45 g of methyl 4-fluoro-5-nitro-2-vinylbenzoate and 104.5 mL of pyridine was added 14.69 mL of tert-butylamine, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to the residue were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 14 g of methyl 4-(tert-butylamino)-5-nitro-2-vinylbenzoate as a brown oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccc(C(N)=O)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with 4-aminobenzamide (1.4 g, 10.0 mmol). Purification on silica gel, eluting with 9:1 CH2Cl2 /MeOH sat'd w/ NH3, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 122 as a white solid (m.p. 275-276° C.).
Reaction SMILES: Cl[C:2]1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.C=C1CC[N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])CC1>C(Cl)Cl>[C:22]([O:21][C:19]([N:16]1[CH2:2][CH2:3][C:4]2([O:10][CH2:8]2)[CH2:5][CH2:6]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.1 %

Procedure:
m-Chloroperbenzoic acid (1.14 g, 6.6 mmol) was added to a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (1 g, 5.1 mmol) in CH2Cl2 (30 mL) at 0° C. The reaction mixture was stirred for 15 h at rt, diluted with CH2Cl2, washed with a saturated aqueous solution of NaHCO3 and brine, dried (Na2SO4), and evaporated to afford 1.1 g of the title compound which was used without further purification. 1H-NMR (400 MHz, CDCl3) δ ppm 3.74-3.65 (m, 2H), 3.45-3.38 (m, 2H), 2.68 (s, 2H), 1.82-1.75 (m, 2H), 1.48-1.41 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.N=C=N.C1C=CC2N(O)N=NC=2C=1.[NH2:22][C@H:23]([C:33]1[NH:34][C:35]([C:38]2[C:39]([O:48][CH3:49])=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:36][N:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30].C(O)C(N)(CO)CO>C(Cl)Cl.CN(C=O)C>[CH3:49][O:48][C:39]1[C:38]([C:35]2[NH:34][C:33]([C@@H:23]([NH:22][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[N:37][CH:36]=2)=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1
Reactant: O=C(O)c1cncs1
Reactant: CNC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Reaction time: 0.17 h

Procedure:
A glass tube was charged with thiazole-5-carboxylic acid (1.5 eq.), PS-carbodiimide resin (2 eq.), HOBt (1.7 eq.) and diluted with DCM (0.04 M). The tube was capped and stirred on a rotor for 10 min. Then, a solution of A4 in DMF (0.06 M) was added and the reaction mixture was stirred in a rotor for 24 h. After addition of MP-Trisamine resin (10 eq.) the reaction was stirred for additional 24 h. The resulting reaction mixture was filtered through a fritted syringe and washed with DCM. The combined organic solutions were concentrated under reduced pressure to give the title compound. MS (ES+) C25H28N6O3S: 493 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1
Yield: 93.2 %

Procedure:
2-Bromobenzene (80 mg, 0.51 mmol) reacted with 2-methylphenylboronic acid (90 mg, 0.66 mmol) using 1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.55 mmol) in THF solvent at room temperature to give the title compound (80 mg, 95%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.51-7.47 (m, 2H), 7.44-7.40 (m, 3H), 7.36-7.32 (m, 4H), 2.36 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 141.91, 141.89, 135.30, 130.27, 129.76, 129.16, 128.03, 127.22, 126.72, 125.73, 20.46. GC/MS(EI): m/z 168 (M+), 153.
Reaction SMILES: CC([N:5]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:18]=[C:17]([NH:30][CH3:31])[N:16]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:32].O1CCOCC1>>[ClH:32].[NH2:5][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[C:17]([NH:30][CH3:31])[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)[CH2:10]1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@@H](N(C(=O)[O-])C(C)(C)C)C2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@@H](N)C2)n1

Procedure:
To 1,1-dimethylethyl{(3R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-3-piperidinyl}carbamate (0.544 g, 1.28 mmol) was added HCl in dioxane (4 mL, 16.00 mmol) at room temperature with stirring. A precipitate immediately formed. The mixture was stirred at room temperature overnight, and then concentrated to dryness to afford an HCl salt of the title compound (0.539 g) as an off-white solid. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH:30]4[CH2:32][CH2:31]4)=[O:28])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:35]#[N:36])C1C=CC=CC=1>[C].[Pd].O1CCCC1>[CH3:33][C:22]1[C:21]([CH3:34])=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([C:35]#[N:36])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH:30]1[CH2:31][CH2:32]1)=[O:28]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
After adding N-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2,3-dimethylphenyl]-N′-cyclopropylurea (1600 mg) to tetrahydrofuran (400 ml), palladium-carbon (2000 mg) was further added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The palladium-carbon was removed by filtration, washing was performed with dimethylformamide, and the filtrate was concentrated under reduced pressure to obtain the title compound (827 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[S:30]([CH3:33])(=[O:31])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(N(CCCCO)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1

Procedure:
5.7 g (12 mmol) of ethyl 4-[(6-benzyloxy-2,2-dimethylchroman-4-yl)-methanesulfonylamino]-N-butyrate (Ex. 28f) were treated with 10 ml of 1 M lithium aluminum hydride solution in THF in 100 ml of THF at 0° C. The mixture was treated at RT with a little water, then with 1N hydrochloric acid, and concentrated, and the residue was extracted three times using EA. After drying and concentrating, the product crystallized overnight. 4.9 g were obtained, m.p. 113-115° C. (from PE/DIPE)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:16])=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:16][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:7]=2)=[CH:14][N:13]=[C:12]([NH2:15])[CH:11]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(N)ncc1Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 60.7 %

Procedure:
5-(2-chloropyridin-4-yloxy)-4-methylpyridin-2-amine (0.116 g, 0.492 mmol) was dissolved in DMF (2 ml) and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (0.154 g, 0.738 mmol) was added, followed by cesium carbonate (0.481 g, 1.477 mmol) and water (0.667 ml). Argon was bubbled through the mixture for several minutes, and then palladium tetrakistriphenylphosphine (0.028 g, 0.025 mmol) was added. The flask was fitted with a reflux condenser, flushed with argon, and heated under a balloon of argon at 90° C. for 16 hours. The mixture was then cooled to RT, and the solution was diluted with a 4:1 mix of ethyl acetate and THF (70 mL). It was washed with 10% aqueous LiCl (2×50 mL) and brine (50 mL), dried (MgSO4), evaporated in vacuo and purified via silica gel chromatography (DCM/MeOH) to yield 4-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine as a clear oil (0.084 g, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.11 (d, 1H), 6.50 (dd, 1H), 6.38 (s, 1H), 5.89 (s, 2H), 3.84 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(#N)C>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: Cc1ccc(CN)cc1
Solvent: CC#N
Product: Cc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccncc3)[nH]2)cc1

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate and 4-methylbenzylamine were dissolved in acetonitrile (80 ml). The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-(4-methylphenyl)-5-(4-pyridyl)imidazole-4-carboxylate.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][C:25](O)=[O:26].CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][C:25](=[O:26])[CH2:24][CH2:23][N:22]([CH3:28])[CH3:21])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: CN(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)CCC(=O)O/N=C(\N)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by the method of Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], 3-(dimethylamino)propanoic acid [Papapoulos, et al, WO 9619998A1], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-[3-(dimethylamino)propanoyl]oxy-2-piperidinecarboximidamide as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][N:15]=2)[C:11]=1O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[N:10]2[N:13]=[CH:14][N:15]=[C:9]2[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ncnn2c1O
Product: CCOC(=O)c1cnc2ncnn2c1Cl

Procedure:
A suspension of 6-ethoxycarbonyl-7-hydroxy-s-triazolo [1,5-a]pyrimidine (7 g) in phosphorus oxychloride (20 ml) was refluxed for 30 minutes, the resultant orange solution was further refluxed for one hour, and excess phosphorus oxychloride was removed by distillation under reduced pressure. Benzene (50 ml) was added to the residue, and remaining phosphorus oxychloride was completely removed by azeotropic distillation under reduced pressure. Chloroform (80 ml) was added to the residue, the insoluble matters were filtered off, and the solvent was removed in vacuo from the filtrate. Purification of the brown residue by silica gel column chromatography gave 3.9 g of the objective compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Reactant: NCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1
Product: Cc1ccc(Cl)c(OCC(O)CNCCc2nc3ccc(C4=NNC(=O)CC4)cc3[nH]2)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)[CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[C:5]([C:14](OCC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].NN>C(O)C.C(Cl)Cl>[N:8]1([C:7]2[S:6][C:5]3[C:14](=[O:15])[NH:21][CH2:20][CH:19]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:33]=4)[C:4]=3[C:3]=2[C:1]#[N:2])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CN1C(=O)c2ccccc2C1=O)c1ccc2ccccc2c1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c(N2CCOCC2)sc2c1C(c1ccc3ccccc3c1)CNC2=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 4-cyano-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(2-naphthyl)ethyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (0.126 g, 0.223 mmol) in ethanol (4.0 mL) and methylene chloride (1.0 mL) was added hydrazine (23.3 mg, 0.727 mmol). After 40 h of stirring at rt, hydrazine (25 mg, 0.78 mmol) was added and the mixture was stirred at rt for another 22 h. The mixture was filtered and concentrated. Purification on a silica gel column (continuous gradient of MeOH/DCM 0-20%) to afford a white solid product (0.0672 g, yield 77.1%). LCMS: (FA) ES+ 390. 1H NMR (400 MHz, d-chloroform) δ: 7.86-7.71 (m, 3H), 7.59 (s, 1H), 7.50-7.42 (m, 2H), 7.37 (dd, J=8.5, 1.8 Hz, 1H), 5.79 (d, J=4.0 Hz, 1H), 4.32 (d, J=3.5 Hz, 1H), 4.19-4.07 (m, 1H), 3.85-3.74 (m, 4H), 3.62 (ddd, J=12.5, 4.5, 2.3 Hz, 1H), 3.59-3.51 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][N:55]1[CH:59]=[C:58]([C:60](Cl)=[O:61])[CH:57]=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:58]2[CH:57]=[N:56][N:55]([CH3:54])[CH:59]=2)=[O:61])[CH2:48]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)cn1
Yield: 72 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-4-carbonyl chloride as the starting materials in 72% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z=558.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:4][CH2:3]1>[Pd].CO.O1CCOCC1>[NH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzotrifluoride (4.0 g) and 10% palladium on activated carbon (400 mg) in a mixture of methanol (20 mL) and dioxane(20 mL) was stirred under hydrogen atmosphere (3 atm) at ambient temperature for 4 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). The obtained substance was triturated with petroleum ether to give 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (3.5 g) as a pale orange solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([NH:23][C:24]3[C:25]([CH3:43])=[CH:26][CH:27]=[C:28]4[C:33]=3[N:32]=[CH:31][N:30]=[C:29]4[NH:34][C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=CC=1>C(O)(C(F)(F)F)=O>[N:12]1[C:13]([C:17]2[C:18]([NH:23][C:24]3[C:25]([CH3:43])=[CH:26][CH:27]=[C:28]4[C:33]=3[N:32]=[CH:31][N:30]=[C:29]4[NH:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]2[C:9]([NH:8][CH:16]=[N:15]2)=[N:10][CH:11]=1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)ncnc45)ncnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1Nc1ncccc1-c1ncnc2[nH]cnc12
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(8-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile (91 mg, 154 μmol) in TFA (3 mL) was heated at 70° C. for 3 h. The TFA was removed in vacuo and 2M NH3/MeOH was added. The mixture was stirred for 5 min and solvent was removed in vacuo. The product was purified by flash chromatography eluting with MeOH(NH3)/DCM (2-6%) to give 4-(8-(3-(9H-purin-6-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 471.2 [M+H]+
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[CH:11]=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]2)=[O:19])[CH:11]=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cnc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)cnc1C
Yield: 80 %

Procedure:
Phenyl-N-(5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.