Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40](C=O)=[CH:39][CH:38]=1.[B-]C#N.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][CH2:21][C:40]3[CH:43]=[CH:44][C:37]([C:36]([F:46])([F:45])[F:35])=[CH:38][CH:39]=3)[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@]1(CN2CCC(NCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
Tert-butyl (S)-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate prepared in Example 283 (0.300 g, 0.787 mmol) was dissolved in methylene chloride (4 ml). To the solution, trifluoroacetic acid (2 ml) was added followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and added methylene chloride (4 ml) and triethylamine (4 ml). The mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-trifluoromethylbenzaldehyde (0.164 g, 0.945 mmol), sodium cyanotrihydroborate (0.099 g, 1.57 mmol) and acetic acid (0.09 ml, 1.57 mmol) were added followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phases were combined, washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) and recrystallized from isopropyl alcohol to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-4-trifluoromethylbenzylamine (0.078 g, yield 22%) as a light yellow powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([CH2:29][C:28](=[O:30])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: O=C1CC2(CCNCC2)Oc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CC(=O)c3ccccc3O4)nn2)n1

Procedure:
The object product (29 mg, 31%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (50 mg), spiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride (60 mg) and potassium carbonate (50 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[CH:3]=1.CCN(CC)CC.[C:27](Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:19])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCCCCC1(c2ccccc2)CC(O)=C(Cc2ccccc2)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-n-pentyl-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2) to provide an oil (0.215 g). 1H NMR (400 MHz, DMSO-d6) δ 10.850 (bs, 1 H), 7.367-7.287 (m, 5 H), 7.018-7.002 (m, 3 H), 6.724-6.700 (m, 2 H), 3.380 (AB, 2 H, JAB =14 Hz), 3.096 (AB, 2 H, JAB =17 Hz), 1.950-1.820 (m, 2 H), 1.230-1.100 (m, 5 H), 1.080-0.920 (in, 1 H), 0.775 (t, 3 H, J=7 Hz).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]([NH:17][NH2:18])=[O:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[K+]>CO.O>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:15]3[O:16][C:2]([NH2:1])=[N:18][N:17]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: N#CBr
Reactant: COc1ccc(C2(C(=O)NN)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2(c3nnc(N)o3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Cyanogen bromide (0.424 g, 4.0 mmol) was added to an ice-cooled slurry of 1-(4-methoxyphenyl)cyclopropanecarbohydrazide (0.750 g, 3.64 mmol) and potassium bicarbonate (0.50 g, 5.0 mmol) in methanol (8 mL). The mixture was stirred at 0° C. for 1 h. the ice bath was allowed to warm slowly and stirred at RT for overnight. The reaction mixture was diluted with water (10 mL), stirred for 1 h. The precipitate was collected by filtration and washed with water, and dried on high vacuum to afford the desired product (600 mg, 71.3%). Analytical LCMS: (M+H)+=232.1.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.C1C=NC=C(C2NC(C(F)(F)F)=CN=2)C=1>>[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:29](=[O:30])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:38][CH2:37]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: CN1CCC(N)CC1
Agent: FC(F)(F)c1cnc(-c2cccnc2)[nH]1
Product: CC(C(=O)NC1CCN(C)CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-methylpiperidin-4-amine (ABCR and Cat. No. MK534). LCMS (M+H)+: m/z=570.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23](C)(C)[CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.O1CCOCC1.CCN(CC)CC.ClC(OCC)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OCC)C3)C2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 92.7 %

Procedure:
LCMS (Method A): m/z 367 (M+H)+ (ES+), at 1.97 min, UV inactive. tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.080 g, 0.22 mmol) was stirred in DCM (10 mL) at rt and treated with 4 M HCl/dioxane (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was conc. in vacuo to give a yellow solid that was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.066 g, 0.1 mL, 0.66 mmol) and ethyl chloroformate (0.036 g, 0.03 mL, 0.32 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 8% MeOH in DCM]) to give ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.069 g, 93%) as an amber oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>Cl>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 1.56 g (10.6 mmol) methyl-malonic acid monoethyl ester in 20 ml of tetrahydrofuran 1.06 g (10.6 mmol) of 2,2,2-trifluoroethylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HCl (50 ml) and afterwards extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by column filtration (hexane/ethyl acetate=2:1) to yield 1.48 g (61%) of the title compound as white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.O.[NH2:28][NH2:29]>C1COCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:28][NH2:29])=[O:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc2c(O)ncnc2c1
Reactant: NN
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1ccc2c(O)ncnc2c1
Reaction time: 18 h

Procedure:
(4-Hydroxy-quinazolin-7-yl)-carboxylic acid (0.5 g) in dry THF (20 ml) was treated with carbonyl diimidazole (0.85 g) under nitrogen for 6 hours at room temperature. Hydrazine hydrate was added and stirring was continued for 18 hours. The mixture was filtered to give the title compound (0.41 g); m/z (M+1+) 205.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([CH3:9])=[C:6]([F:8])[CH:7]=1>C(O)C.O.Cl.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[C:4]([NH2:10])[CH:3]=1
Reactant: Cc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(N)cc(Br)cc1F

Procedure:
A mixture of 5-bromo-1-fluoro-2-methyl-3-nitro-benzene (9.96 g) and iron powder (11.9 g) in ethanol (100 ml), water (20 ml) and concentrated hydrochloric acid (2 ml) was heated at reflux for one hour. After cooling, the reaction mixture was filtered through hyflo (calcined diatomaceous earth) and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:9 to 1:4). Yield: 7.06 g of 5-bromo-3-fluoro-2-methyl-phenylamine as an oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:22][CH2:21]2)[C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[C:14]([C:13]1[C:16]([CH:20]2[CH2:22][CH2:21]2)=[CH:17][CH:18]=[CH:19][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])#[N:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1c(N)cccc1C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#Cc1c(NS(=O)(=O)c2ccccc2)cccc1C1CC1
Reaction time: 5 h
Yield: 39.4 %

Procedure:
Benzenesulfonyl chloride (0.093 g) was added to a solution of 2-amino-6-cyclopropyl-benzonitrile (Intermediate 10, 0.07 g) in DCM (4 mL) and pyridine (0.1 mL). The mixture was stirred for 5 hours, then a further aliquot of benzenesulfonyl chloride (0.093 g) was added together with triethylamine (0.12 mL) and the mixture was stirred overnight. The reaction mixture was washed with water, and the organic solution was dried with magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless oil (0.052 g).
Reaction SMILES: O[C:2]1([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12>C(Cl)(Cl)Cl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][CH:16]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12
Reactant: CN(C)CCCC1(O)c2ccccc2CCn2cccc21
Solvent: ClC(Cl)Cl
Product: CN(C)CCC=C1c2ccccc2CCn2cccc21
Reaction time: 0.08 h

Procedure:
Hydrogen chloride gas is bubbled through a solution of 4.8 gm. (0.017 moles) of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine in 70 ml. of chloroform at 0° C. for 5 minutes. The resulting dark mixture is stirred for an additional 5 minutes, and then washed with 6M NaOH to provide, after evaporation of the chloroform, 4.3 g. of 11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine as an oil. It is converted to a crystalline oxalate by adding a solution of 266 mg. of the free base in 5 ml. of ethanol to a mixture of 90 mg. of oxalic acid and 2 ml. of ethanol and collecting the precipitate by filtration and air drying; m.p. 140°-165° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200 mg, 0.68 mmol, 1.00 equiv), benzofuran-2-ylboronic acid (220 mg, 1.36 mmol, 1.99 equiv), Pd(PPh3)4 (157 mg, 0.14 mmol, 0.20 equiv), K3PO4 (577 mg, 2.73 mmol, 4.01 equiv), and 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 160 mg (63%) of methyl 2-(benzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O1CCCC1>CO.[Pd]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c(F)c1N
Yield: 108.4 %

Procedure:
A mixture of methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (40.0 g, 173.7 mmol) and 5% Pd/C (3.0 g, Type 487; 0.4 mol % Pd relative to starting material), in methanol (300.0 mL) and tetrahydrofuran (300.0 mL) was stirred at 2000 RPM, under hydrogen (−3.5 bar), at 50° C. in a 1.5 L hydrogenation vessel. After 6 hours the vessel was purged with nitrogen and HPLC analysis indicated that no starting material remained. The mixture was then filtered under nitrogen pressure and the filter washed through with THF (160 mL), to give a clear yellow solution. The solvent was removed by rotary evaporation, to provide methyl 2,4,5-triamino-3-fluorobenzoate (9) 37.5 g (93.3% w/w by NMR) as a solid, yield ˜100%. 1H NMR (400 MHz, d6 DMSO) δ 3.69 (3H, s, NMe), 4.20 (2H, br s, NH2), 5.24 (2H, br s, NH2), 5.70 (2H, br s, NH2), 6.83 (1H, d, J 1, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 51 (CH3), 98 (C, d, J 5), 110 (CH, d, J 2), 125 (C, d, J 6), 131 (C, d, J 12), 133 (C, d, J 12), 139 (CF, d, J 225), 166 (C═O). νmax/cm−1 3480, 3461, 3373, 3356, 3280, 3163, 1679, 1655, 1314. MS APCI (+) m/z 200 (M+1) detected.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:19][CH2:20][O:21][CH3:22].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:19][CH2:20][O:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]=1[CH3:7]
Reactant: Cc1c(I)cnn1CC1(O)CCCCC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCCOC1(Cn2ncc(I)c2C)CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 101B (260 mg) in tetrahydrofuran (15 mL) was added NaH (97 mg). The mixture was stirred for 30 minutes. 1-Bromo-2-methoxyethane (564 mg) was added to the mixture and the mixture was stirred for 3 hours. The mixture was then stirred at reflux for 2 hours. Hexamethylphosphoramide (5 mL) and additional NaH (200 mg) were added to the mixture and the mixture was stirred at reflux overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. The residue, after filtration and evaporation of the solvent, was loaded on a 40 g column and eluted with 20% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][C:8](=[O:10])[NH:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:11][Si:12]([CH3:15])([CH3:14])Cl.O1CCCC1>C(N(CC)CC)C>[C:1]([O:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([Si:12]([CH3:15])([CH3:14])[CH3:11])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CNC(=O)C1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC1CC(=O)N([Si](C)(C)C)C1
Reaction time: 1 h

Procedure:
10.0 g. of 5-oxo-3-pyrrolidinyl acetate and 8.82 ml. of trimethylchlorosilane are dissolved in 100 ml. of absolute tetrahydrofuran and then 9.65 ml. of triethylamine are added at -5° C. to 0° C. The temperature is held at -5° C. to 0° C. for 1 hour, the mixture is then filtered under an argon atmosphere, the filtrate is evaporated and the residue is distilled in vacuo. There is obtained 5-oxo-1-trimethylsilyl-3-pyrrolidinyl acetate, having a boiling point of 110° C./0.07 mmHg.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([CH2:16][CH2:17][NH:18]C(=O)OCC2C=CC=CC=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[BrH:29]>C(O)(=O)C>[BrH:29].[NH2:18][CH2:17][CH2:16][N:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2](=[O:1])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: O=C(NCCn1c2ccccc2c(=O)c2ccccc21)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCCn1c2ccccc2c(=O)c2ccccc21
Reaction time: 1 h

Procedure:
A suspension of 11.2 g of benzyl [2-(9-oxo-10(9H)-acridinyl)ehtyl]carbamate in 100 ml of glacial acetic acid is treated with 20 ml of hydrogen bromide-containing glacial acetic acid (about 30 percent) and stirred for 1 hour. The product is filtered and washed with glacial acetic acid and ether. There is obtained 10-(2-aminoethyl)-9-acridanone hydrobromide of melting point >250°. The free base is precipitated from an aqueous solution with sodium bicarbonate solution, filtered and washed with water and acetone. The hydrochloride obtained therefrom and analyzed melts above 250°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:29]#[C:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#Cc1ccccc1
Yield: 18.9 %

Procedure:
40 mg 2-[(1-Bromo-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester and 2 mg Bis(triphenylphosphine)palladium(II) chloride were suspended in 2 ml of DMF and deoxygenated with Argon. 0.26 ml of TMEDA were added, the mixture was again bubbled with Argon, and then 14 mg (0.137 mmol) phenylacetylene were added. After 14h at 80° the reaction was filtered, purified by RP-HPLC and freeze-dried to give 8 mg of 2-{[1-(Phenylethynyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester (19%).
Reaction SMILES: C([N:8]1[CH:13]2[C:14](=[O:29])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:16](=[O:17])[CH:9]1[CH2:10][S:11][CH2:12]2)C1C=CC=CC=1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>[OH-].[OH-].[Pd+2].CO>[F:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[C:16](=[O:17])[CH:9]3[NH:8][CH:13]([CH2:12][S:11][CH2:10]3)[C:14]2=[O:29])=[CH:23][CH:22]=1
Reactant: O=C1C2CSCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [OH-]
Solvent: CO
Product: O=C1C2CSCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 16 h

Procedure:
A mixture of 9-benzyl-7-(4-(trifluoromethoxy)phenyl)-3-thia-7,9-diazabicyclo[3.3.1]nonane-6,8-dione (143 mg, 0.34 mmol), 20% Pd(OH)2/C (243 mg, 0.35 mmol Pd), methanol (10 mL), and 1N HCl (3 mL) were shaken under 60 psi of H2. After 16 h, more 20% Pd(OH)2/C (250 mg, 0.36 mmol Pd) was added, and the reaction was shaken under 90 psi of H2. After an additional 24 h, the reaction was filtered through Celite, concentrated, and then partitioned between ethyl acetate (50 mL) and sat'd NaHCO3 (50 mL). The organic extract was dried, filtered, concentrated, and purified by silica gel chromatography (2:3→0:1; hexanes:ethyl acetate) to give 7-(4-(trifluoromethoxy)phenyl)-3-thia-7,9-diazabicyclo[3.3.1]nonane-6,8-dione: MS (ESI): 333.4 (M+H).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CCN(C(C)C)C(C)C>>[N:16]1[C:17]2[C:12](=[CH:11][C:10](/[CH:9]=[C:5]3/[C:6](=[O:8])[N:7]=[C:3]([NH:25][C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[S:4]/3)=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: Nc1nccs1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(Nc2nccs2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, thiazol-2-ylamine and DIEA to give 5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-2-(thiazol-2-ylamino)-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 340 (MH+).