Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[C:4](#[N:8])/[CH:5]=[CH:6]/[CH3:7].[C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.C(O[Na])(C)(C)C>C1COCC1.O>[C:9]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:10]=[CH:11][C:12]([CH2:15][N:2]2[C:4]([NH2:8])=[CH:5][C:6]([CH3:7])=[N:3]2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: C/C=C/C#N
Agent: CC(C)(C)O[Na]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)n(Cc2ccc(-c3ccccc3)cc2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
(see, e.g., WO2009150614A1). To a solution of hydrazine monohydrate (hydrazine 78-82%) (0.51 ml, 10.5 mmol) in THF (2 mL), crotononitrile (mixture of cis and trans) (0.82 ml, 10.1 mmol) was added dropwise. The mixture was stirred at 40° C. for 2 h. The mixture was allowed to cool to room temperature and biphenyl-4-carboxaldehyde (1.82 g, 10.0 mmol) was added. The mixture was stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure. To the resulting yellow solid was added iPrOH (15 mL) and the suspension was transferred to a pressure vessel. t-BuONa (993 mg, 10.3 mmol) was added and the mixture was stirred at 100° C. for 2 h 30 min. The mixture was allowed to cool to room temperature and diluted with water (50 mL). The mixture was extracted with Et2O (50 mL×2). The combined organic layers were extracted with IN aq. HCl (2×30 mL). The combined aqueous phases were basified to pH 14 with 50% aq. NaOH and extracted with Et2O (50 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound (885 mg, 34% over three steps) as a yellow solid. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, DMSO-d6) δ 7.68-7.61 (m, 4H), 7.45 (t, J=7.5 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.37-7.33 (m, 1H), 5.59 (s, 1H), 5.38 (s, 2H), 2.20 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 151.46, 146.77, 140.52, 139.98, 134.32, 129.40, 128.62, 128.09, 127.51, 127.14, 91.23, 48.92, 11.54.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a 3-neck, 1-liter, round-bottom flask was added 2-methylimidazole (41.0 g, 0.50 mole), 4-bromoanisole (100 g, 0.53 mole) and potassium carbonate (96.0 g, 0.70 mole) in N-methyl-2-pyrrolidinone (300 ml). A small amount of cuprous chloride (2.5 g) was added. The stirred reaction mixture was heated at reflux temperature for 24 hr and then the N-methyl-2-pyrrolidinone and excess bromoanisole gently distilled. The black pot residue was partitioned between toluene and water and a black solid removed by filtration. The toluene layer was extracted with 48% hydrobromic acid (2×200 ml) and the hydrobromic acid solution was heated at reflux temperature 3 hr then stirred at room temperature overnight. The solution was then concentrated, diluted with water (500 ml) and made basic with sodium hydroxide and sodium bicarbonate solutions. The white solid which precipitated was collected and dried and a small amount recrystallized from methanol/isopropyl alcohol. The total yield was 24.88 g (28.6% yield), mp 205°-208° C.
Reaction SMILES: C(O[C:6]([N:8]([CH3:25])[CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=C=O)=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:6]([N:8]([CH3:25])[CH:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:7])=[CH:36][CH:35]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc3cc(Cl)ccc23)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Nc1ccc(F)cc1)C1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
A solution of 4-[3-[tert-butoxycarbonyl(methyl)amino]pyrrolidin1-yl]-7-chloroquinoline (285 mg, 0.79 mmol) in CH2Cl2 (5 mL) is treated with trifluoroacetic acid (1 mL). After 1 h the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (10 mL), and 4-fluorophenyl isocyanate (90 μL, 0.79 mmol) and triethylamine (1 mL) are added. The reaction mixture is concentrated, and the residue is purified by column chromatography and an aqueous work-up step yielding the title product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19].[Br:30][C:31]1[C:32]2[C:36]([CH:37]=[CH:38][CH:39]=1)=[CH:35][NH:34][CH:33]=2>CN(C)C(=O)C>[Br:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][N:34]([C:18]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)=[O:19])[CH2:35]2
Reactant: Brc1cccc2c[nH]cc12
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Br)c3C2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution containing 0.5 g of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2 mmol) in 5 mL of N,N-dimethylacetamide, was added 370 mg of carbonyl diimidazole (1.1 equiv.). The reaction was heated at 60° C. for 1 hr, then 400 mg of 4-bromoisoindole (2 mmol) was added. The reaction was continued at 60° C. overnight. After cooling down, the reaction mixture was extracted with 50 mL of EtOAc, and washed with water, brine, and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography on silica gel using heptanes/EtOAc (v/v 5/2), giving white solid 745 mg (79%). LC-MS: m/z=369.2 (ES+, M+1-Boc).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH:6]=[CH:5][CH2:4]1.[C:15](OC(N[C@@H](CCC=C)C(O)=O)=O)(C)(C)C>>[ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH:6]=[CH:5][CH2:4][CH2:15]1
Reactant: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Reactant: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: N[C@H]1CC/C=C\[C@H]2CCCCN2C1=O
Product: N[C@H]1CCC=C[C@H]2CCCCN2C1=O

Procedure:
(7S,11aR,Z)-7-Amino-3,4,7,8,9,11a-hexahydro-1H-pyrido[1,2-a]azocin-6(2H)-one hydrochloride (538 mg, 2.332 mmol) was synthesized as described for the preparation of Intermediate 53 using (S)-2-(tert-butoxycarbonylamino)hex-5-enoic acid in step E. Anal. Calcd. for C11H18N2O m/z 194.2. found: 195.0 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C[Si]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](O[Si](C(C)(C)C)(C)C)[C:31]=1[CH:44]1[CH2:49][CH2:48][C:47](=[CH2:50])[CH2:46][CH2:45]1)(C(C)C)C)(C)(C)C.[O:51]1CCCC1>>[CH2:50]=[C:47]1[CH2:48][CH2:49][CH:44]([C:31]2[CH:32]=[CH:33][C:34]([OH:51])=[CH:35][C:30]=2[OH:29])[CH2:45][CH2:46]1
Reactant: C=C1CCC(c2c(O[Si](C)(CC(C)(C)C)C(C)C)cccc2O[Si](C)(C)C(C)(C)C)CC1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=C1CCC(c2ccc(O)cc2O)CC1
Reaction time: 24 h
Yield: 90 %

Procedure:
Tetrabutylammonium fluoride (230 μl) was added to a stirred solution of tert-butyl-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy](isopropyl)dimethylsilane (40 mg) in tetrahydrofuran (2 ml) at room temperature. After 24 hr, further tetrabutylammonium fluoride (50 μl) was added, and after 2 hr the solvent was removed under reduced pressure. The residue was partitioned between water (20 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 2:3 v/v) to give the title compound as a white solid (17 mg, 90%). δH(CD3OD) 1.25-1.40 (2H, m), 1.75-1.82 (2H, m), 2.04-2.15 (2H, m), 2.22-2.30 (2H, m), 2.86 (1H, tt), 3.20 (1H, m), 4.50 (2H, s), 6.10-6.16 (2H, m), 6.72 (1H, d); m/z (ES+) 205 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH:18](O)=[O:19]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][CH:18]=[O:19])=[C:3]([CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=CO
Product: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
2-Amino-5,2'-dichlorobenzophenone is reacted with formic acid, whereby 5, 2'-dichloro-2-formylaminobenzophenone (pale yellow granules melting at 106° to 107° C) is obtained. The product is then reacted with hydrazine hydrate, whereby 3-amino-6-chloro-4-(2-chlorophenyl)-3,4-dihydro-4-hydroxyquinazoline (colorless granules melting at 198° C (effervescence)) is obtained. The product is reacted with chloroacetyl chloride, whereby a bis-(monochloroacetyl) derivative of 3-amino-6-chloro-4-(2-chlorophenyl)-3,4-dihydro-4-hydroxyquinazoline (colorless powdery crystals melting at 157° to 158° C) is obtained. Further, the product is treated with monochloroacetic acid in dry benzene under refluxing, whereby crystals of 2-(3-chloromethyl-s-triazol-4-yl)-5, 2'-dichlorobenzophenone are obtained. Recrystallization from chloroform-n-hexane gives colorless granules melting at 139° to 140° C. Overall yield: 34%.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([F:18])([F:19])[F:20])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/C(F)(F)F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(/C=C/C(F)(F)F)cc1F

Procedure:
A solution of (E)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate (500 mg, 0.002 mol) in CH2Cl2 (10 mL) and TFA (1.0 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a white solid. LC-MS: 2.99 min, 233.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.200 g (0.405 mmol) of the product from Example 26 in CH2Cl2 (4 mL) at 0° C. was treated with trimethylacetyl chloride (50 μL; 0.405 mmol) followed by triethylamine (113 μL; 0.810 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 578.0 (M+1), 580.0 (M+3); Rt=4.69 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:24]=[C:23]([CH2:22][Cl:21])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: CN1Cc2c(C(N)=S)ncn2-c2cccc(Cl)c2C1=O
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2cccc(Cl)c2C1=O
Yield: 87.1 %

Procedure:
A yellow suspension of 10.3 g (0.0336 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 220 ml of dioxan was treated with 4.69 g (0.0370 mol) of 1,3-dichloro-2-propanone. The solution was boiled at reflux for 16 hrs., cooled and suction filtered. There were obtained 11.1 g (87%) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as brown crystals. An analytical sample was recrystallized from hot acetonitrile. White crystals; m.p. 277-279°.
Reaction SMILES: Br[C:2]1[CH2:6][C:5](C)(C)[CH2:4][C:3]=1[Br:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)CC(Br)=C(Br)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=C(Br)CCC2)cc1
Yield: 24.1 %

Procedure:
Under nitrogen, 1.3 g (5.1 mmol) of 1,2-dibromo-4,4-dimethylcyclopentene (Step 8) was reacted with 600 mg (4.3 mmol) of 4-fluorophenylboronic acid (Lancaster) in 23 mL of toluene, 15 mL of ethanol, and 10 mL of 2M Na2CO3 in the presence of 250 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 250 mg of 1-(2-bromocyclopenten-1-yl)-4-fluorobenzene (38 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R3, R4, R6, and R7 =H) as a pale yellow oil which was reacted with 200 mg (1.2 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1) in 5.2 mL of toluene, 3.4 mL of ethanol, and 2.2 mL of 2M Na2CO3 in the presence of 40 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux for 6 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 120 mg of 1-[2-(4-fluorophenyl)-4,4-dimethyl cyclopenten-1-]-4-(methylthio)benzene (41 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R10 =SCH3, R3, R4, R6, R7, R8, R9, R11, and R12 = H) as an oil: NMR (CDCl3) d 1.20 (s, 6H0 2.42 (s, 3H), 2.63 (s, 4H), 6.90 (t, J=8 Hz, 2H), 7.00-7.60 (m, 4H), 7.30-7.60 (m, 2H).
Reaction SMILES: C(=[C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[CH:7][NH:6]1)C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C=C1NC=CC=C1CN
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1cccnc1
Yield: 2062.8 %

Procedure:
The procedure is carried out as in Example 1(b) but with the use of 80.1 g (0.495 mol) of isobutylidene-3-aminomethylpyridine, 2.5 g (0.0223 mol) of potassium tert-butylate and 75 ml of toluene. After a reaction time of 1 hour at 30°-35° C., distillation yields 74.5 g (0.46 mol) of 3-pyridylmethylidene-isobutylamine; yield 93% of theory; b.p. 108° C./2×103Pa; nD20 =1.5198.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:3]=[C:2]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Clc1nc(N2CCOCC2)c2nc(Cl)c(N3CCOCC3)nc2n1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Clc1nc2c(N3CCOCC3)nc(N3CCNCC3)nc2nc1N1CCOCC1

Procedure:
9.3 g (0.025 mol) of 2,6-dichloro-4,7-dimorpholino-pteridine were refluxed for one hour with 8.6 g (0.1 mol) of anhydrous piperazine in 200 ml of dioxane. The solvent was substantially distilled off, and the residue was digested with about 100 ml of water. After the aqueous mixture stood for a short time, it was suction-filtered, and the filter cake was washed with water and dried at about 70° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1.C[N:27](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC1N=CC2CCC3C=C(OC)C=CC=3C=2N=1>CN(C=O)C>[NH2:1][C:2]1[C:6]([C:7]([NH2:27])=[O:9])=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Agent: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(N)=O)c(N)n3)nc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-amino-1-(8-methoxy-5,6-dihydrobenzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid 1 (0.084 g, 0.25 mmol), HBTU (0.113 g, 0.3 mmol) and DIEA (0.18 mL, 1 mmol) in DMF (1 mL) was added amine 2 (0.3 mmol). Resulting reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, solvent was removed on rotavap and residue was purified by preparative HPLC to give 3-amino-1-(8-methoxy-5,6-dihydrobenzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic amide 3.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[CH:15]=[N:16][N:17]2[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:20](=[O:41])[N:19]([CH:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[C:18]=12>C(OCC)(=O)C>[CH3:13][C:14]1[CH:15]=[N:16][N:17]2[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:3][C:4](=[O:7])[O:5][N:40]=4)=[CH:31][CH:32]=3)[C:20](=[O:41])[N:19]([CH:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[C:18]=12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with 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 amorphous solid (0.2 g, 58%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:35])([F:34])[C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([C:28]5([C:27]([F:35])([F:34])[F:26])[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1(C(F)(F)F)CC1

Procedure:
The title compound, white solid (10 mg, 31.5%), MS (ISP) m/z=467.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1>C(Cl)Cl>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:19][CH2:20][CH:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1)(=[O:16])=[O:15]
Reactant: OCC1COc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
Triethylamine (4.2 ml, 30 mmol was added, in one portion, and then, in portions, para-toluenesulfonyl chloride (5.7 g, 30 mmol was added, to a solution of 2-hydroxymethyl-1,4-benzodioxane (Maybridge, 5 g, 30 mmol) in methylene chloride (50 ml). A mild exothermic reaction ensued. The reaction mixture was stirred overnight. Precipitated triethylamine hydrochloride was separated by filtration and washed with methylene chloride (50 ml). The organic medium was washed with 10% aqueous hydrochloric acid (50 ml , water 50 ml , brine (30 ml), and dried over sodium sulfate. Purification of the crude product by column chromatography (400 g fine silica, hexane-ethyl acetatetriethylamine; 100:100:1) yielded pure (1,4-benzodioxan-2-yl)methyl tosylate (66%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([Br:20])=[CH:4][N:3]=1
Reactant: Nc1nccc2cc(F)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
To a solution of 1-amino-6-fluoro-isoquinoline (0.41 g, 2.53 mmol) in CHCl3 (25 mL) is added NBS (0.45 g, 2.53 mmol), and the reaction mixture is stirred RT for 1.5 h. The reaction mixture is treated with water (10 mL). The aqueous phase is extracted with CH2Cl2 (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (10-40% MeOH/CH2Cl2) afforded 0.395 g (65%) of 1-amino-4-bromo-6-fluoro-isoquinoline. LC/MS m/z=242 [M+H]+.