Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:24].C(N(C(C)C)C(C)C)C.Cl[C:35]1[N:40]=[N:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:35]4[N:40]=[N:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=4)[C:3]3=[O:24])[CH2:8][CH2:9]2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)nn1
Temperature: 90 °C
Yield: 14.6 %

Procedure:
To a solution of (S)-3-amino-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.15 g, 0.41 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.160 g, 1.24 mmol) and 6-chloropyridazine-3-carbonitrile (0.173 g, 1.24 mmol) and the reaction was heated to 90° C. overnight. The reaction was diluted with EtOAc (150 mL) and washed with water (100 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The material was purified on silica, using 1:1 EtOAc:DCM as eluent to yield a solid, which was further triturated with diethyl ether to yield (S)-6-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylamino)pyridazine-3-carbonitrile (0.028 g, 0.060 mmol, 14% yield). Mass spectrum (apci) m/z=466.0, 467.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][C@H:28]1[CH2:33][C@@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:30]4[CH2:31][C@H:32]([CH3:34])[CH2:33][C@H:28]([CH3:27])[CH2:29]4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Product: C[C@@H]1C[C@H](C)CN(Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1

Procedure:
Prepared analogously to Example 1.2.c. from (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide and cis-3,5-dimethylpiperidine. Yield: 30 mg (30% of theory); melting point: 217° C.-218° C.; C29H31ClN2O (M=459.03); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:22]=[N:23][C:18]3=[N:17][CH:16]=2)[CH:12]=[N:11]1.O1CCOCC1.Cl>C(Cl)Cl>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([CH2:24][N:21]3[C:19]4[C:18](=[N:17][CH:16]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)[N:20]=4)[N:23]=[N:22]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1cnc2ccc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: OCCn1cc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (780 mg, 1.71 mmol) in CH2Cl2 (20 mL) was added the anhydrous HCl dioxane solution dropwise (4N, 1.07 mL, 4.27 mmol). A white solid was precipitated out. The reaction mixture was stirred for 1 hour and the LCMS showed the completion of the reaction. The reaction mixture was concentrated, and the residue was dissolved in distilled water (15 mL). The solution was adjusted to pH 7 with Na2CO3. An off-white solid was crashed out, which was filtered, washed with water, and dried on a high vacuum for 1 hour. The solid was re-crystallized from EtOH (50 mL) to provide 2-[4-(3-Quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (400, 63% yield) as a white crystalline solid with a melting point of 222° C. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H) 8.89 (dd, J=4.14, 1.70 Hz, 1H) 8.63 (s, 1H) 8.37 (dd, J=8.38, 1.04 Hz, 1H) 8.32 (s, 1H) 7.98-8.04 (m, 2H) 7.82 (dd, J=8.67, 2.07 Hz, 1H) 7.53 (dd, J=8.29, 4.14 Hz, 1H) 6.15 (s, 2H) 4.96 (t, J=5.27 Hz, 1H) 4.24 (t, J=5.46 Hz, 2H) 3.78 (q, J=5.46 Hz, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].[CH2:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][C:10](=[O:19])[N:9]3[CH2:8]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.Cl>CC(C)=O.O>[N:25]1[CH:26]=[CH:27][C:22]([C:21]([C:15]2[CH:14]=[C:13]3[C:18]4=[C:17]([CH2:7][CH2:8][N:9]4[C:10](=[O:19])[CH2:11][CH2:12]3)[CH:16]=2)=[O:28])=[CH:23][CH:24]=1
Reactant: O=C1CCc2cccc3c2N1CC3
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccncc1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a molten mixture of AlCl3 (8.0 g, 60.0 mmol) and NaCl (2.34 g, 40.0 mmol) at 150° C. was added 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.79 g, 10.0 mmol) and thereafter isonicotinoylchloride hydrochloride salt (1.96 g, 11.0 mmol) portionwise. After stirring for 15 min and cooling to room temperature, excess aluminum chloride was decomposed by the addition of a chilled mixture of 10 ml concentrated hydrochloric acid and 200 ml water. Neutralization with NaHCO3 solution and subsequent extraction with ethyl acetate (3×100 ml), followed by drying over MgSO4 and removal of the solvent gave the crude product. Purification by crystallization from acetone gave the acylation product (751 mg, 2.70 mmol, 27%) as a yellow solid, mp (acetone) 184° C. 1H-NMR (500 MHz, CDCl3): δ=2.70 (t, 3J=7.7 Hz, 2H), 2.99 (t, 3J=7.8 Hz, 2H), 3.21 (t, 3J=8.2 Hz, 2H), 4.12 (t, 3J=8.2 Hz, 2H), 7.49 (m, 3H), 7.55 (s, 1H), 8.76 (d, 3J=5.1 Hz, 2H), 13C-NMR (125 MHz, CDCl3): δ=24.1, 27.2, 31.3, 45.7, 119.9, 122.6, 126.1, 129.0, 129.4, 131.4, 145.3, 146.3, 150.2, 167.8, 193.9. MS m/z 279.07 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:8]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.CCO[C:28]([C:30]([NH2:32])=[O:31])=[O:29].Cl>CCO>[C:28]1(=[O:29])[N:32]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[NH:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[C:8]=3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:5][CH2:6]2)[C:30]1=[O:31]
Reactant: Fc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CCOC(=O)C(N)=O
Agent: Cl
Solvent: CCO
Product: O=c1c(=O)n1N1CCC(c2[nH]nc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Reaction time: 16 h

Procedure:
To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole (Example C-2) (0.11 g, 0.35 mmol) in 2 mL EtOH was added ethyl acetamidate hydrochloride (0.065 g, 0.53 mmol) and the mixture was refluxed for 30 minutes. The solution was left at 5-10° C. for 16 h and filtered to obtain the title compound as a white solid: MS (M+H): 364 (base peak).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](CCCC#N)[CH:2]=1.[N:12]1C=[CH:16][C:15](CCCBr)=[CH:14][CH:13]=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:16][CH2:15][CH2:14][C:13]#[N:12])=[CH:5][CH:6]=1
Reactant: N#CCCCc1cccnc1
Reactant: BrCCCc1ccncc1
Product: N#CCCCc1ccncc1
Yield: 51 %

Procedure:
4-Pyridinebutanenitrile was prepared according to the procedure employed in the synthesis of 3-pyridinebutanenitrile. From 73.1 g of the hydrobromide salt of 3-(4-pyridyl)propyl bromide there was obtained 19.35 g (51%) of 4-pyridinebutanenitrile, bp 140°-141° C./2.0 mm.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CN1CCC(N)CC1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Br)cn1
Solvent: CN1CCCC1=O
Product: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Br)CC1
Yield: 99 %

Procedure:
A solution of N-(5-bromo-4-chloropyridin-2-yl)pivalamide (0.547 g, 1.87 mmol), 1-methylpiperidin-4-amine (0.600 g, 5.25 mmol) in NMP (3.3 mL) was heated under microwave irradiation for 3 hr at 220° C. The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless oil (0.684 g, 99%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:41]([OH:46])(=[O:45])[CH2:42][CH:43]=[CH2:44].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[CH2:42][C:41]([OH:46])=[O:45])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 57.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole (3.0 g) and 3-butenoic acid (1.0 g) in acetonitrile (15 mL) were added triethylamine (2.4 g), palladium acetate (II) (0.11 g) and tris(2-methylphenyl)phosphine (0.29 g), and the mixture was refluxed overnight under shading the light. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give the title compound (1.74 g).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (0.29 g, 3.3 mmol) and triethyloxonium tetrafluoroborate (0.61 g, 3.2 mmol) in THF (5.6 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (2.4 mL) and added to a suspension of tert-butyl ({trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl)carbamate (0.30 g, 0.80 mmol) in ethanol (8.6 mL). The mixture was stirred at 85° C. for 2 h. The mixture was concentrated and purified with flash chromatography (0-10% methanol/dichloromethane) to give the desired product (0.21 g, 61%). LCMS calculated for C22H31N4O3S (M+H)+: m/z=431.2. Found: 431.1.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(O)CC(=O)OC(CCc2ccc(O)cc2)C1
Yield: 61.6 %

Procedure:
To a solution of 5.65 g of 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-5-heptanolide in 50 ml of ethyl acetate was added 2.0 g of 5% palladium-charcoal and the mixture was subjected to a catalytic hydrogenation. After filtration the solvent was evaporated to give crystals, which were recrystallized from a mixture of n-hexane and acetone (5:1) affording 2.56 g of the desired compound melting at 135°-137° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-])=O>C1COCC1.Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9][C:8]=2[CH:15]=1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a stirred solution of 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (0.5 g, 0.002 mol) in THF (125 mL) was added stannous chloride in conc. HCl (4 mL) over a 5 minute period. During this time the reaction mixture got very hot but not to reflux. The reaction mixture was stirred at room temperature for 2 h. The mixture continued to stir at room temperature overnight. HPLC showed no starting material remaining. The reaction mixture was concentrated in vacuo to remove all of the volatiles and the residue dissolved in water and made basic with 6N sodium hydroxide. The suspension was filtered through celite and washed well with chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-amino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (0.32 g, 70% yield). 1HNMR (400 MHz, DMSO-d6) δ 6.87 (d, 1H, J=8 Hz), 6.46 (s, 1H), 6.38 (d, 1H, J=8 Hz), 4.83 (s, 2H), 2.68 (m, 4H), 2.44 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([O:40]C)=[O:39].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([OH:40])=[O:39]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(N2CCN(c3cccc(F)c3)CC2)=Nc2c(F)cccc2C1CC(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In 15 ml of dioxane, 117 mg (0.2 mmol) of methyl {8-fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 34A) are mixed with 0.61 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred at 50° C. for 3 hours. After removal of the solvent, the residue is taken up in water and the mixture is adjusted to pH 3-4 using 1N hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 437.13 g/mol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C(Cl)[Cl:11]>S(Cl)(Cl)=O>[Cl:11][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: ClCCl
Reactant: Cc1ccc(CO)cn1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (6-methylpyridin-3-yl)methanol (13 g) in DCM (260 mL), thionyl chloride (13 mL) was added slowly under nitrogen at RT. The mixture was stirred at RT for 1 h, the reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was concentrated under reduced pressure, the residue was suspended in saturated aq. NaHCO3 (pH 8) and extracted with DCM (2×100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to obtain 12.5 g of product as a yellow oil.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([O:14]C)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1.O>ClCCl>[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([OH:14])[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c(C=O)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)c(C=O)c1O
Yield: 95.1 %

Procedure:
1 M boron trichloride in dichloromethane (25 ml; 25 mmol) was added to a solution of 6-fluoro-2,3-dimethoxy-benzaldehyde [Cantrell, Amanda S.; Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; et al.; J. Med. Chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23 mmol) in dichloromethane (30 ml) keeping the reaction temperature at −70 C. The reaction mixture stirred at room temperature overnight and hydrolyzed with water. The organic phase was separated, washed with water and evaporated in vacuo. The residue was chromatographed (silica gel, EA:Hex, 5:1) to give 3.72 g (94%) of 6-fluoro-2-hydroxy-3-methoxy-benzaldehyde as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10]>O1CCCC1>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH:14][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)[CH3:10]
Reactant: CCOC(CN)OCC
Reactant: Cc1nc(CCl)cs1
Solvent: C1CCOC1
Product: CCOC(CNCc1csc(C)n1)OCC
Reaction time: 16 h
Yield: 76 %

Procedure:
4-Chloromethyl-2-methylthiazole (0.6 g, 4 mmol) was added to aminoacetaldehyde diethyl acetal (5 mL, 10 equivalents) dissolved in tetrahydrofuran (15 mL) at 25° C., and the mixture was stirred for 16 h. The solvents were evaporated and the excess aldehyde was distilled from the crude mixture. The crude residue was purified using dichloromethane—dichloromethane/10% methanol to give 0.76 g (76%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[C:12]1([CH2:11][O:18][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-isonicotinic acid [CAS Reg. No. 6313-54-8] (4 g) and benzyl alcohol (3.3 g) were added to dry toluene (50 mL). Sodium hydride (2.66 g, 50% in mineral oil) was added in 2 portions and the mixture was allowed to stir at room temperature for 30 minutes. 18-Crown-6 (906 mg) was added and the mixture was then heated to 125° C. for 12 hours. An unstirrable, yellow mixture was obtained. This was diluted with more toluene (80 mL) and stirring was continued for another 4 hours at 125° C. TLC analysis confirmed that there was still 2-chloro-isonicotinic acid left. More benzyl alcohol (3.3 g) and sodium hydride was (2.66 g) added and the mixture was heated for another 12 hours. The mixture was cooled and quenched with 1M aqueous HCl (100 mL). Hexane (200 ml) was added and the mixture was stirred at 0° C. for 1 hour; a light brown solid was obtained. The solid was filtered off and washed with hexane. To remove residual water from the solid, toluene was added and removed again. A colorless solid was obtained (4.8 g). MS (m/e, ISP neg ion): 228.3 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]2[CH2:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)([OH:15])[C:6]3=[C:7]([F:12])[CH:8]=[N:9][C:10]([CH:11]=1)=[C:5]23.Cl>ClCCl.CO.O1CCOCC1>[NH2:23][CH:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2([OH:15])[C:6]3=[C:7]([F:12])[CH:8]=[N:9][C:10]4[CH:11]=[C:2]([Cl:1])[C:3](=[O:31])[N:4]([C:5]=43)[CH2:14]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of crude 1,1-dimethylethyl {1-[((4R/S)-8-chloro-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (˜1 g, 2 mmol) in dichloromethane/methanol (20 mL/20 mL) was treated with a 4M solution of HCl in 1,4-dioxane ((20 mL) was stirred at room temperature, under argon, for 30 min. The reaction mixture was evaporated, dissolved in water (˜10 mL), basified by addition of solid sodium carbonate and evaporated. The residue was stirred with a 15% solution of methanol in dichloromethane (3×200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and chromatographed eluting with a gradient of dichloromethane and 2M ammonia/methanol affording the product (215 mg, 27%).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:13])[CH2:6][CH2:5]1)=O.C(Cl)Cl>C(N(CC)CC)C>[O:13]=[C:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:4]([N+:3]#[C-:1])[CH2:5][CH2:6]1
Reactant: O=CNC1CCC(=O)c2sccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]C1CCC(=O)c2sccc21
Reaction time: 0.75 h

Procedure:
A sample of N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine (5.0 g) is dissolved methylene chloride (250 ml) under a nitrogen atmosphere and triethylamine (5.95 g) is added. Phosgene is then bubbled into the solution at 15° C and an exothermic reaction occurs. The temperature of the reaction mixture rises from 20° to 35° C and after 45 minutes, drops to 30° C. The flow of phosgene is terminated and nitrogen is then bubbled into the solution for about 20 minutes followed by ammonia gas. A brown precipitate is formed during the ammonia addition. The flow of ammonia gas is stopped when the reaction mixture becomes alkaline. The mixture is then flushed with nitrogen and is filtered to remove the precipitate. The filtrate is evaporated to dryness in vacuo, the residue is dissolved in ethanol (50 ml), the solution is filtered and evaporated to dryness in vacuo. The residue is scratched to afford a light brown solid, which is washed with water, dried and recrystallized from hexane-acetone to afford 2.1 g of the title isocyanide, m.p. 74° to 77° C.