Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH:2]([CH3:4])[CH3:3]>CS(C)=O>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:6]=[N:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C=NCc1cccc(Oc2ccccc2)c1
Solvent: CS(C)=O
Product: CC(C)CN=Cc1cccc(Oc2ccccc2)c1
Yield: 95 %

Procedure:
51 g (0.202 mol) of N-isobutylidene-(3-phenoxybenzylamine) is dissolved in 45 ml of dimethyl sulfoxide, and at room temperature (20°-25° C.) is added all at once, with stirring, 2 g (0.0179 mol) of potassium-tert-butylate. The temperature of the reaction solution rises during this addition to 25°-30° C. The solution is stirred for a further hour at room temperature, and is then extracted three times with 50 ml of water each time. The residue is taken up in 30 ml of diethyl ether, dried with magnesium sulfate, and distilled to obtain 48.5 g (0.192 mol) of 3-phenoxybenzylidene-isobutylamine, corresponding to a yield of 95% of theory; b.p. 83° C./4 Pa; nD20 =1.5677.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][C:17]#N)=[O:14])=[O:8])(=[O:3])[CH3:2].[O:29](CCO)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][CH2:17][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: OCCOc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCC#N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCCOc2ccccc2)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 51.9 %

Procedure:
Cyanomethyl 3-[(2 acetylthiomethyl-3-phenylpropionyl)amino]benzoate (compound of Example 116) (4 g), 2-phenoxyethanol (3 g), 4-dimethylaminopyridine (0.1 g) and triethylamine (2 g) are mixed, and the mixture is stirred at 60° C. for 15 hours and extracted with ethyl acetate (50 ml). The extract is washed with 10% hydrochloric acid and water, and ethyl acetate is distilled off under reduced pressure. The residue is dissolved in 50% aqueous acetonitrile and purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate (100 ml). The extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give the title compound (2.5 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Solvent: CO
Product: COC(=O)CC1NC(=O)c2ccccc21
Reaction time: 3.5 h

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (described by F. M. Rowe et al., cited above, 130 g, 0.682 mol) in methanol (1300 ml) containing 6.5 g of p-toluenesulfonic acid is refluxed with stirring for 3.5 hr. Most of the methanol is evaporated and the residue is dissolved in chloroform. The solution is washed with 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue (125 g) is crystallized from isopropanol to give methyl 1,3-dihydro-3-oxo-2H-isoindole-1-acetate, mp 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1)(=[O:17])=[O:16]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Yield: 84.4 %

Procedure:
3-Methylsulfonylamino-5-nitro-1H-indazole can be obtained as described in Example 2 from 0.7 g of 3-amino-5-nitro-1H-indazole, 23 ml of pyridine and 0.455 g of methylsulfonyl chloride. 0.85 g of 3-methylsulfonylamino-5-nitro-1H-indazole is thus obtained in the form of an orange powder used as it is in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1.CCOC(C)=O>[C:24]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2F)ccn1
Reaction time: 0.75 h
Yield: 67.7 %

Procedure:
A tert-butyl 4-(2-aminopyridin-4-yloxy)-3-fluorophenylcarbamate (150 mg, 0.47 mmol) in anhydrous pyridine (0.5 mL) was cooled to 10° C. and treated with acetyl chloride (33 μL, 0.47 mmol) and the mixture stirred for 45 min. An additional portion of acetyl chloride (16 μL, 0.24 mmol) was added to the reaction and stirring continued for 25 min. The mixture was diluted with EtOAc (20 mL), washed with brine, dried (MgSO4) and concentrated under vacuum to give the title compound (115 mg, 68%). 1H NMR (DMSO-d6) δ 10.55 (s, 1H), 9.71 (s, 1H), 8.16 (d, 1H, J=5.5 Hz), 7.63-7.55 (m, 2H), 7.29-7.23 (m, 2H), 6.68-6.63 (m, 1H), 2.02 (s, 3H), 1.48 (s, 9H); MS(ESI+): m/z 362.22 (M+H)+.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl[C:30]1[N:35]=[C:34]([NH:36][CH3:37])[N:33]=[C:32]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]([F:57])([F:56])[F:55])=[O:45])[CH2:40][CH2:39]2)[N:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:37][NH:36][C:34]1[N:35]=[C:30]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:31]=[C:32]([N:38]2[CH2:39][CH2:40][CH:41]([C:44]([NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]([F:57])([F:55])[F:56])=[O:45])[CH2:42][CH2:43]2)[N:33]=1
Reactant: OB(O)c1ccccc1
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 150 °C

Procedure:
A 5 ml microwave vial was charged with palladium (II) acetate (0.38 mg, 0.0017 mmol, 0.010 equiv), tricyclohexylphosphine (0.95 mg, 0.0034 mmol, 0.020 equiv), and phenyl boronic acid (30.9 mg, 0.253 mmol, 1.50 equiv). A premixed solution of 1,4-dioxane (0.875 ml) and 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide was added, followed by a premixed solution of water (0.125 ml) and potassium phosphate tribasic (71.7 mg, 0.338 mmol, 2.00 equiv). The reaction was heated via a microwave reactor for 20 min at 150° C. The reaction was diluted with water (5 ml) and extracted three times with ethyl acetate (5 ml). The ethyl acetate extracts were combined, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1.5 ml DMSO and purified via reverse-phase HPLC purification to afford the title compound. MS (ES+): m/e 470.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:12]1[C:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[S:14][C:13]=1[N:15]1[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[NH:17][C:16]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1ccccc1-2

Procedure:
A mixture of 49 mg (0.12 mmol) of 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione from Example 485, and 0.0334 ml (0.24 mmol) of triethylamine in 5 ml of ethanol was hydrogenated over 120 mg of 10% palladium on charcoal at 1 atm for 3 hours. The mixture was filtered through celite and concentrated in vacuum. The residue was purified on 4 g siligal column eluting the product with ethyl acetate gradient in heptane to give 493. Yield 20 mg (51%). MS (ESI+): 330.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:15](S(C3C=CC=CC=3)(=O)=O)[C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 99.2 %

Procedure:
A solution of 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.34 g, 2.11 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 8.0 mL, 8.0 mmol) was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.04 g, quant.) as a white solid: LC/MS m/e calcd for C27H32N2O5S [M+H]+ 497.63, observed 497.4.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 1-[4′-(trifluoromethyl)-4-biphenylyl]-1-pentanone (500 mg, 1.63 mmol) in THF (16 mL) and water (8 mL) under nitrogen at 0° C. (ice/water bath) was added sodium borohydride (74 mg, 1.96 mmol) portion-wise. After stirring the mixture for 1 hour at rt, the reaction was diluted with water (30 mL) and extracted into EtOAc (3×30 mL). The combined organic extract was separated, dried (MgSO4) and reduced under vacuum to afford the title compound as a colourless gum (490 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(NC(C)CC(C)C)C>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: CCNC(C)CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. Next, N-ethyl-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in the ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (about 3 L). The filtrate was concentrated and the residue was purified over silica gel (3 kg silica, 7:1 to 3:1 Hex/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle and washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: ClC1C=C(N2C(C3C=CC(C(F)(F)[F:20])=CC=3)=NOS2=O)C=CC=1.ClC1C=C(N2C(C3C(Cl)=CC=CC=3Cl)=NOS2=O)C=CC=1.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[N:53]1[C:57]([C:58]2[CH:63]=[CH:62][C:61](Cl)=[CH:60][CH:59]=2)=[N:56][O:55][S:54]1=[O:65].ClC1C=C(Cl)C=CC=1N1C(C2C=CC(Cl)=CC=2Cl)=NOS1=O.ClC1C=C(Cl)C=CC=1N1C(C2C(Cl)=CC=CC=2Cl)=NOS1=O>>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[N:53]1[C:57]([C:58]2[CH:63]=[CH:62][C:61]([F:20])=[CH:60][CH:59]=2)=[N:56][O:55][S:54]1=[O:65]
Reactant: O=S1ON=C(c2ccc(Cl)cc2)N1c1ccc(Cl)cc1Cl
Reactant: O=S1ON=C(c2ccc(C(F)(F)F)cc2)N1c1cccc(Cl)c1
Agent: O=S1ON=C(c2c(Cl)cccc2Cl)N1c1ccc(Cl)cc1Cl
Agent: O=S1ON=C(c2c(Cl)cccc2Cl)N1c1cccc(Cl)c1
Agent: O=S1ON=C(c2ccc(Cl)cc2Cl)N1c1ccc(Cl)cc1Cl
Product: O=S1ON=C(c2ccc(F)cc2)N1c1ccc(Cl)cc1Cl

Procedure:
3-(3-chlorophenyl)-4-(4-trifluoromethylphenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(3-chlorophenyl)-4-(2,6-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(4-chlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(3-chlorophenyl)-4-(2,4-chlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(4-trifluorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(2,4-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(2,6-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide.
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.CO.[H][H]>[Pd].CCCCCC>[NH2:1][C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6]
Reactant: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCCCCC
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Temperature: 2.5 °C

Procedure:
2-nitro-2-(4-octylphenethyl)propane-1,3-diol (3 g) and methanol (60 mL) are charged into a hydrogenation vessel at 25-30° C. and stirred. 10% Pd/C (0.6 g) is charged into the vessel, a hydrogen pressure of 4-5 Kg/cm2 applied and the reaction mixture is maintained under the same conditions for about 5 hours. The reaction mixture is filtered through a hyflow bed and washed with methanol (10 mL). The obtained filtrate is concentrated under reduced pressure at a temperature below 36° C. to obtain 8 mL of concentrated reaction mass. n-Hexane (50 mL) is added, the reaction mixture is cooled to 0-5° C. and maintained at the same temperature for about 1 hour. The solid obtained is filtered, washed with n-hexane (10 mL) and dried under vacuum at 36° C. to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[CH:6][C:5]=1[CH3:15])(=O)[CH3:2].[BH4-].[Na+].[OH-].[NH4+:19]>N.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:19][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[CH:6][C:5]=1[CH3:15])[CH3:2]
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(C(C)(C)C#N)cc1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: N
Solvent: CO
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a stirred solution of 2-(4-acetyl-3-methylphenyl)-2-methylpropanenitrile (1.0 g, 4.97 mmol) in 7 M ammonia in MeOH (40 mL) is added titanium (IV) isopropoxide (3.0 g, 9.95 mmol). The reaction mixture is left stirring 24 h at room temperature. After cooling to 0° C., sodium borohydride (1.0 g, 19.9 mmol) is added and the reaction mixture stirred and left to warm-up to room temperature 1 h. Conc. ammonium hydroxide (15 mL) is then added and the titanium oxide is removed by filtration and is washed with ethyl acetate. The filtrate is extracted with EtOAc (2×100 mL) and the combined organic layers are dried over MgSO4, filtered and concentrated under reduced to provide the expected product 2-[4-(1-aminoethyl)-3-methylphenyl]-2 methylpropanenitrile (1.0 g, 99%) as a clear yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.33 (d, J=6.64 Hz, 3H) 1.44 (s, 2H) 1.70 (s, 6H) 2.36 (s, 3H) 4.34 (q, J=6.44 Hz, 1H) 7.22 (d, J=1.95 Hz, 1H) 7.28 (dd, J=8.20, 2.15 Hz, 1H) 7.48 (d, J=8.20 Hz, 1H)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]([C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[CH:34]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=[C:31]([O:29][CH3:30])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc(OC)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3,5 dimethoxylbenzaldehyde. MS (ESI) m/z 522.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[C:13]1(N)[C:18]([F:19])=[C:17](F)[C:16](F)=[C:15]([NH2:22])[C:14]=1F.Cl.Cl>>[F:19][C:18]1[CH:13]=[CH:14][C:15]2[NH:22][C:11]3[CH2:10][CH2:5][N:4]([CH2:2][CH2:1][C:3]4[CH:12]=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH2:3][C:12]=3[C:16]=2[CH:17]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: C=Cc1ccc2ccccc2n1
Agent: Cl
Product: Fc1ccc2[nH]c3c(c2c1)CN(CCc1ccc2ccccc2n1)CC3

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception that 2-vinylquinoline was used instead of 2-vinylpyridine. The product was converted to the dihydrochloride salt; mp 192°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH2:26][CH2:27][O:28]C4CCCCO4)[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH2:26][CH2:27][OH:28])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CCOC2CCCCO2)on1
Agent: Cl
Solvent: CCO
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CCO)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Into a solution containing N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxamide (0.04 g, 0.083 mmol) and ethanol (4 ml), hydrogen chloride, 10% in EtOH (0.5 ml, 1.350 mmol) was added. The resulting mixture was stirred for 2 h at RT. The mixture was evaporated, 2 ml of diethyl ether was added and stirred. The precipitated product was filtered and washed with cold heptane. The product was pure enough without further purifications. Yield 85%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 2.92 (t, 2H), 3.69 (t, 2H), 4.29-4.34 (m, 2H), 4.41-4.50 (m, 1H), 6.51-6.53 (m, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.09 (d, 1H), 8.73 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>C(#N)C>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([S:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(S(=O)(=O)c1cccs1)CC2
Temperature: 60 °C
Reaction time: 7 h
Yield: 92.4 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry acetonitrile (15 mL) was treated with dry triethylamine (0.11 mL), then with 2-thiophenesulfonyl chloride (52 mg). After stirring at 60° C. for 7 hours the reaction mixture was allowed to cool to room temperature and then stand overnight. The solvent was removed under reduced pressure and the residue then treated with water and dichloromethane. The organic phase was separated, then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) to give 7-chloro-6-phenyl-2-(thiophene-2-sulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (100 mg) as a white solid, m.p. 240–242° C. [Elemental analysis: C, 50.95; H, 4.06; N, 9.98%; Calculated for C18H16ClN3O3S2: C, 51.24; H, 3.82; N, 9.96%].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][C@H:30]([CH2:34][OH:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][C@H:30]([CH2:34][OH:35])[CH2:29]2)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: OC[C@@H]1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 23.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol hydrochloride (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.25 g, 23%). The compound was characterized by the following spectroscopic data: