Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])(=[O:40])=[O:39])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1S(=O)(=O)NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added 2-methoxybenzenesulfonyl chloride (0.096 mmol, 19.91 mg) and the whole stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a white solid (13.0 mg, 0.027 mmol, 28%). [M+H]+ 482.2.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:21][CH:20]=2)[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.[C:33](=[NH:38])(OCC)[CH3:34].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[C:33]([N:29]1[CH2:28][CH2:27][CH:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([N:15]([CH2:14]/[CH:13]=[CH:12]/[C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[NH:4])[NH2:5])[CH:7]=3)[C:16](=[O:18])[CH3:17])=[CH:24][CH:23]=2)[CH2:31][CH2:30]1)(=[NH:38])[CH3:34]
Reactant: CC(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 157.1 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]acetamide dihydrochloride (400 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (320 mg) and triethylamine (0.60 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 15% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (342 mg, yield 79%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[Cl:12][C:13]([Cl:17])([CH3:16])[CH:14]=O.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH2:14][C:13]([Cl:17])([Cl:12])[CH2:16][C:4]2([CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH2:8]2)[C:5]([NH2:7])=[O:6])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NC(=O)C1(CC(Cl)(Cl)Cn2nnc3ccccc32)C=C(F)C=C(F)C1

Procedure:
3,5-Difluorobenzamide, the product from Example 24A, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12]Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:16][N:17]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:22]=[N:21][C:20]=2[N:19]([CH3:37])[C:18]1=[O:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:16][N:17]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]([OH:36])[CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH2:12][CH2:11][CH2:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH2:34][CH2:35]3)[CH:22]=[N:21][C:20]=2[N:19]([CH3:37])[C:18]1=[O:38]
Reactant: Cn1c(=O)c2c(ncn2CC(O)CN2CCNCC2)n(C)c1=O
Reactant: O=S(=O)(CCCCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCS(=O)(=O)c3ccccc3)CC2)n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.13 Moles of 3-phenylsulfonyl-1-chloropropane were combined with 0.14 moles of 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]piperazine dihydrochloride and 0.3 moles potassium carbonate in 600 grams dimethylformamide. The mixture was stirred overnight at 60° C. After cooling, the reaction mixture was poured into water, extracted with CH2Cl2, washed with water, dried, and evaporated with gentle heating. The residue was recrystallized from ethanol to give the free base form of 1-[3-(1,3-Dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-phenylsulfonylpropyl)piperazine, m.p. 168° C. The dihydrochloride was obtained by adjunction with 12N hydrogen chloride solution as described in Example III, m.p. 190° C.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][S:5][C:6]=1[NH:7][C:8]([C@@H:10]1[CH2:12][C@H:11]1[CH3:13])=[O:9].[CH2:20]([Li])CCC.CI>C1COCC1>[CH3:13][C@@H:11]1[CH2:12][C@H:10]1[C:8]([NH:7][C:6]1[S:5][N:4]=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]=1[CH3:20])=[O:9]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccccc2)c1Br
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)nsc1NC(=O)[C@@H]1C[C@H]1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To (R,R)—N-[4-bromo-3-phenylisothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.50 g, 1.48 mmol) in THF (3 mL), cooled to −78° C., is added 1.1 equivalent n-butyllithium (n-BuLi) (1.6M in hexane, 0.204 mL, 3.26 mmol). Internal temperature is maintained below −68° C. Following addition, the reaction mixture is allowed to stir for 1 h. 1.1 additional equivalents of n-BuLi (1.6M in hexane, 0.204 mL, 3.26 mmol) is then added while keeping the internal temperature below −66° C. After stirring for 2 h, the reaction mixture is warmed to −40° C. for 15 min; and then cooled back down to −78° C. Methyl iodide (0.10 mL, 1.63 mmol) is then added. The reaction mixture is allowed to warm to room temperature and stir over a weekend before the reaction is quenched with satd NH4Cl and diluted with EtOAc. The organic phase is washed with brine, dried (K2CO3) and evaporated. Chromatography over silica gel, eluting with 5-35% EtOAc in hexane, affords (R,R)-2-methyl-N-(4-methyl-3-phenylisothiazol-5-yl)-cyclopropanecarboxamide. Yield: 16.4%. ES-MS: 273.2 (m+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18](OCC)=[O:19])=[CH:12][CH:11]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][C:42]([CH3:44])=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:18](=[O:19])[C:17]([CH2:16][C:13]4[CH:12]=[CH:11][C:10]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][C:7]([F:9])=[CH:6][CH:5]=5)=[CH:15][CH:14]=4)=[C:23]([CH2:24][CH2:25][CH3:26])[N:40]4[N:41]=[C:42]([CH3:44])[N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccc(F)cc2C#N)cc1)C(=O)OCC
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-4′-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (2.9 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.93 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) and N,N-diethylaniline (30 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.1 g, 48%).
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20]3)[N:17]=[CH:18][C:8]1=2)[CH3:6].[H][H]>[Pd].C(O)C>[CH2:5]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[N:17]=[CH:18][C:8]1=2)[CH3:6]
Reactant: CCN1C(=O)CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN1C(=O)CCCc2nc(N3CCNCC3)ncc21
Reaction time: 4 h
Yield: 100 %

Procedure:
To a mixed solvent of 30 ml of acetic acid and 10 ml of ethanol, 0.6 g (2.18 mmol, Referential Example 52) of 5-ethyl-2-(4-benzylpiperazino)-6-oxo-6,7,8,9-tetrahydro(5H)pyrimido[5,4-b]azepine and 0.06 g of 10% Pd-C were added. While causing hydrogen gas to flow through the reaction mixture, the reaction was allowed to proceed at 100° C. for 4 hours. Thereafter, the Pd/C was filtered off and the filtrate was dried to obtain 0.5 g of a light yellowish oily substance (yield: about 100%).
Reaction SMILES: [CH3:1][C:2](=[O:8])[C:3](=O)[C:4](=O)[CH3:5].[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1.C[N:18](C)C=O>>[CH3:5][C:4]1[NH:18][C:15]([C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[N:16][C:3]=1[C:2](=[O:8])[CH3:1]
Reactant: CC(=O)C(=O)C(C)=O
Reactant: NCc1ccncc1
Reactant: CN(C)C=O
Product: CC(=O)c1nc(-c2ccncc2)[nH]c1C
Temperature: -10 °C

Procedure:
A mixture of 6.5 g of 2,3,4-pentanetrione, 3-oxime and 6.0 g of 4-pyridylmethylamine in 75 ml of N,N-dimethylformamide was stirred at reflux temperature for 4 hours, then the solvent was removed in vacuo and 100 ml of acetonitrile was added to the residual oil. This mixture was boiled, then cooled at -10° C. The resulting precipitate was collected, washed with 50 ml of cold acetonitrile, air dried and then recrystallized from 150 ml of boiling acetonitrile after treatment with activated charcoal by cooling at -10° C., giving 4.0 g of the desired compound as a tan solid, mp 181°-183° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>CCOCC>[OH2:8].[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][C:19](=[O:23])[C:20](=[O:21])[O:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCc1ccc2oc(=O)c(=O)oc2c1
Product: O
Temperature: 25 °C
Yield: 165.3 %

Procedure:
A mixture of 3.81 g (25 mM) of 4-n-propylcatechol, 5.06 g (50 mM) of triethylamine and 50 ml of dry ether was cooled in an ice water bath so as to maintain the temperature at 5° C. or below. The mixture was added dropwise over 1.5 hours under stirring with a solution of 3.50 g (28 mM) of oxalyl chloride in 10 ml of dry ether. After completing the dropwise addition, the temperature of the reaction mixture was gradually raised to the room temperature and then aging was conducted for an hour. The resultant mixture was heated under reflux for 3 hours in order to complete the aging. The separated crystals of triethyl ammonium chloride was filtered. After thoroughly washing the crystals with ether, the ether solution was collected and dried with anhydrous sodium sulfate. After distilling off ether, the reaction product was recrystallized from a solvent mixture of carbontetrachloride and petroleum benzine to obtain 4.64 g (22.5 mM) of 6-n-propyl-1,4-benzodioxine-2,3-dione monohydrate as colorless crystals having a melting point of 99°-100° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:16](I)[CH3:17].O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:16]([N:6]1[C:2](=[O:1])[CH2:3][CH2:4][C@H:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:17]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,1-dimethylethyl 5-oxo-L-prolinate (2.7 g, 12 mmol, prepared as described in Synth. Comm., 2005, 35(8), 1129) was added to a suspension of sodium hydride (0.428 g (60% suspension in oil), 10.7 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 5 minutes. Ethyl iodide (1.67 g, 10.7 mmol) was then added and the mixture was heated at 40° C. for 2 hrs. A further quantity of sodium hydride (0.24 g) was added and stirring continued overnight at room temperature. An additional quantity of ethyl iodide (0.86 ml) was added to the mixture at this stage and the mixture was left to stand at room temperature over the weekend. Water (˜10 ml) was added to the mixture and this was stirred for 15 minutes. The tetrahydrofuran was evaporated and the remaining aqueous layer was extracted with dichloromethane (2×50 ml) and a 3:1 mixture of chloroform and isopropanol (50 ml). The combined organic layers were filtered through a hydrophobic frit and evaporated to give a yellow oil. Toluene was added to the mixture and then evaporated to a yellow oil once more. This material was purified by automated silica flash-column chromatography (Biotage SP4), eluting with a 15-100% gradient of ethyl acetate in hexane, to give pure 1,1-dimethylethyl 1-ethyl-5-oxo-prolinate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][CH2:29][C@H:30]([O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([CH:43]=O)=[N:40]2)=[CH:35][CH:34]=1)[CH3:31].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:43]([C:39]3[CH:38]=[CH:37][C:36]4[C:41](=[CH:42][C:33]([O:32][C@H:30]([CH3:31])[CH2:29][O:28][CH3:27])=[CH:34][CH:35]=4)[N:40]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COC[C@@H](C)Oc1ccc2ccc(C=O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC[C@@H](C)Oc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.6 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.17 g, 0.44 mmol) and (R)-7-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (0.11 g, 0.44 mmol) in ethanol (2.2 mL, 0.44 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.2 mL) and iodosobenzene diacetate (0.16 g, 0.49 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.11 g, 42%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]2([OH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1(O)CCCCCCC1
Product: O=C(NCCC(O)c1cccc(C#CC2(O)CCCCCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with 1-ethynyl-cyclooctanol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-(1-hydroxycyclooctyl)ethynyl)phenyl)propyl)acetamide as yellow oil. Yield (0.54 g, 44%). This compound was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1>>[C:7]1([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:1][C:2]5[CH:6]=[C:5]([C:7]6[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=6)[NH:4][N:3]=5)=[O:21])=[CH:17][CH:18]=4)=[CH:27][CH:26]=3)=[O:30])[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: O=C(Nc1cc(-c2ccccc2)[nH]n1)c1ccc(-c2ccc(C(=O)Nc3cc(-c4ccccc4)[nH]n3)cc2)cc1

Procedure:
Compound 475 was prepared from 3-amino-5-phenylpyrazole and biphenyl-4,4′-dicarboxylic acid. [M+H]+ calcd for C32H25N6O2: 525.20; found: 524.98.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CC#N>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19](=[O:20])[NH:10][C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nnc(N)o1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a suspension of 5-tert-butyl-[1,3,4]oxadiazol-2-ylamine (Atlantic, 141 mg, 1.00 mmol) and Et3N (279 μL, 2.00 mmol) in MeCN (2 mL), 2,2,2-trichloroethyl chloroformate (207 μL, 1.50 mmol) was added in 4 portions over 1 min at RT (CARE: exotherm to −40° C.). The resulting suspension was stirred for 1 h. The suspension was filtered, washing the solid with MeCN (3 mL), and concentrated to leave a yellow-brown paste. Purification by FCC, using 0-2.5% MeOH in DCM, gave a buff foam (232 mg, 73%). 1H NMR (400 MHz, CDCl3): 1.42 (9H, s), 4.86 (2H, s).
Reaction SMILES: COC([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:6]=1[C:23]#[N:24])=N.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1.[H-].[Na+].C(O)(=O)C.[CH3:43][N:44](C=O)C>>[CH3:22][O:21][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][C:9]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[N:44]=[CH:43][N:25]([C:26]1[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:30]=1)[C:23]2=[NH:24]
Reactant: COC(=N)c1cc(OCCCN2CCOCC2)c(OC)cc1C#N
Reactant: CN(C)C=O
Reactant: Nc1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2c(=N)n(-c3nc(-c4ccccc4)cs3)cnc2cc1OCCCN1CCOCC1

Procedure:
Methyl-2-cyano-4-methoxy-5-(3-morpholinopropoxy)phenylimidoformate (100 mg; 0.3 mmol) in DMF (1.5 ml) was reacted with 2-amino-4-phenyl-1,3-thiazole (58 mg; 0.33 mmol) in presence of sodium hydride (13.2 mg; 0.33 mmol) at 75° C. for 1.5 h. Acetic acid (1.5 eq.) was added and the solvent was evaporated to give 6-methoxy-7-(3-morpholinopropoxy)-3-(4-phenyl-1,3-thiazol-2-yl)quinazolin-4(3H)-imine as an intermediate which was redissolved in DMF (1.5 ml) and ammonium acetate (95 mg; 0.9 mmol) added. The mixture was stirred at 75° C. for 1 h, the solvent was evaporated and the residue purified by silica gel chromatography, CH2Cl2/MeOH 95/5→90/10 to give title compound (44 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CN1[C:41](=[O:42])[CH2:40][CH2:39]C1.C(Cl)(=O)C=C>C(Cl)Cl>[O:22]([C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH:40]=[CH2:39])[CH:7]=[CH:6][CH:5]=3)[CH:14]=2)[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Agent: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of N4-(3-aminophenyl)-N6-(3-phenoxyphenyl)pyrimidine-4,6-diamine (40 mg, 0.1 mmol), Et3N (0.03 mL, 0.2 mmol) and NMP (0.4 mL) in CH2Cl2 (2 mL), at 0° C., was added acryloyl chloride (6) (29 mg, 0.3 mmol). The reaction mixture was allowed to come to rt and stirred at this temperature for 3 h. It was washed with 10% NaHCO3 solution (2 mL), water (2 mL), brine (2 mL) and dried over Na2SO4. Filtration followed by concentration under reduced pressure offered a residue which was purified by column chromatography (SiO2, 230-400, chloroform/methanol, 9/1) to gave N-(3-(6-(3-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (I-75) as a light brown solid. 1H NMR (DMSO-d6) δ ppm: 5.73 (dd, J=1.72 & 10 Hz, 1H), 6.18 (s, 1H), 6.24 (dd, J=1.92 & 17 Hz, 1H), 6.45 (dd, J=10.04 & 16.88 Hz, 1H), 6.54-6.57 (m, 1H), 7.01-7.05 (m, 2H), 7.11-7.15 (dd, J=0.88 & 7.48 Hz, 1H), 7.19-7.32 (s, 4H), 7.35-7.41 (m, 4H), 7.89 (s, 1H), 8.26 (s, 1H), 9.2 (s, 1H), 9.25 (s, 1H), 10.26 (s, 1H); LCMS: m/e 423.8 (M+1).
Reaction SMILES: C(O)(=O)C(O)=O.C([O:11][C:12](=[O:26])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:15]1=[O:25])(C)(C)C.[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:50](O)=[O:51])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:50]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([OH:11])=[O:26])[C:15](=[O:25])[C@@H:16]1[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:51])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:45]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](Cc1ccc(C(=O)OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
In 7.6 ml of methylene chloride were dissolved 0.76 g of (S)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid t butyl ester oxalic acid salt and 0.47 g of N-benzyloxycarbonyl-4-methoxycarbonyl-L-phenylalanine. To the solution was added gradually, while cooling with water, 0.44 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, over 5 minutes. The mixture was stirred for one hour at room temperature, then methylene chloride was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by means of a silica gel chromatography (hexane/ethyl acetate=l/2) to give 0.46 g (51.1%) of the title compound as a colorless oily product.