Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]3[N:49]=[C:48]([CH2:50][CH2:51][C:52]4[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=4[CH2:59][C:60]([O-])=[O:61])[C:47]([C:63]([F:66])([F:65])[F:64])=[CH:46][N:45]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[Li+].CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[NH2:7][C:60](=[O:61])[CH2:59][C:53]1[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:52]=1[CH2:51][CH2:50][C:48]1[C:47]([C:63]([F:65])([F:64])[F:66])=[CH:46][N:45]=[C:44]([NH:43][C:40]2[CH:39]=[CH:38][C:37]([CH:34]3[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:30])[CH2:32][CH2:33]3)=[CH:42][CH:41]=2)[N:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(F)ccc4CC(=O)[O-])n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(F)ccc4CC(N)=O)n3)cc2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
HOBt (0.024 g, 0.175 mmol) and EDCl.HCl (0.034 g, 0.175 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-fluorophenyl)acetate (A53) (0.089 g, 0.146 mmol) and Et3N (0.082 mL, 0.585 mmol) in DMF (5 mL) and the resulting mixture stirred at 40° C. overnight. Saturated aqueous NaHCO3 (25 mL) and DCM (25 mL) were added then the layers separated and the aqueous phase extracted with CHCl3 (3×25 mL). The organics were combined then the volatiles were evaporated in vacuo. The residue was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to yield a clear oil. The oil was triturated with water and the resulting precipitate collected by filtration to give the title compound A54 as a white solid (0.065 g, 74%); 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=1.0 Hz, 1H), 7.46 (d, J=8.2 Hz, 3H), 7.18-7.09 (m, 3H), 6.95-6.84 (m, 2H), 5.24 (d, J=21.9 Hz, 2H), 4.18 (s, 2H), 3.60 (s, 2H), 3.02 (s, 4H), 2.74 (t, J=10.2 Hz, 2H), 2.58 (m, 1H), 1.76 (d, J=11.7 Hz, 2H), 1.64-1.51 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.477 min; m/z 602 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16](Cl)[C:15]([CH3:20])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.[CH3:23][OH:24].C[O-].[Na+].Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:24][CH3:23])[C:15]([CH3:20])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(Cl)c3C)nc2c1
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 10 h
Yield: 76.6 %

Procedure:
First, 277 mg (0.92 mmol) of 5-methoxy-2-{[(4-chloro-3,5-dimethyl-2-pyridyl)methyl]thio}-1H-benzimidazole obtained in Example 21 and 1.00 g (5.20 mmol) of methanol 28% solution of sodium methoxide were introduced to a 3-necked flask (30 ml volume) equipped with a thermometer, a magnetic stirrer and a condenser tube, and the mixture was agitated for 10 hours while being slowly refluxed. Then the mixture was neutralized with dilute hydrochloric acid. Ethyl acetate (10 ml) was added thereto and an organic layer was separated, and an aqueous layer was extracted twice with 10 ml of ethyl acetate. The extracts and the above mentioned organic layer were combined and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 232 mg of 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio}-1H-benzimidazole (yield of 85%) with revealing the properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[CH2:11][CH2:10][N:9]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[C:11](=[CH:22][N:23]([CH3:25])[CH3:24])[CH2:10][N:9]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN=C(c2ccccc2Cl)c2ccccc21
Product: CN(C)C=C1CN=C(c2ccccc2Cl)c2ccccc2C1=O

Procedure:
A mixture of 3.4 g (12.5 mmole) of 1-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 28 ml of dimethylformamide dimethyl acetal was refluxed for 2 hr. The mixture was concentrated at reduced pressure and the resulting solid was triturated with ether to give a tan solid, mp 155°-157° C. Recrystallization from a mixture of methylene chloride and ether gave yellow prisms, mp 158°-159° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncc(Cl)cc2Oc2ccccc2)n1
Yield: 88.9 %

Procedure:
A mixture of 1-chloropropan-2-one (3.827 g, 41.36 mmol), 1-(5-chloro-3-phenoxypyridin-2-yl)thiourea (8.265 g, 29.54 mmol), triethylamine (7.001 mL, 50.23 mmol), and ethanol (30 mL) was refluxed for 3 hours. The ethanol was removed to about one third original volume, and then the reaction mixture was cooled in an ice bath and filtered. The solids were washed with cold ethanol and dried to afford the title compound (8.35 g, 88.96% yield) as a light yellow powder. 1H NMR (d6-DMSO) δ 10.94 (bs, 1H), 8.15 (d, 1H), 7.43 (t, 2H), 7.32 (d, 1H), 7.20 (t, 1H), 7.19 (d, 2H), 6.60 (s, 1H), 2.23 (s, 3H); Mass spectrum (apci) m/z=318.2 (M+H).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=1)=[O:9])C.[C:24]([SiH2:28][O:29][C:30]([CH3:38])([CH3:37])[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([SiH2:28][O:29][C:30]([CH3:38])([CH3:37])[C:31]1[N:32]=[C:33]([NH:36][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:34][CH:35]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1csc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Agent: C[Al](C)C
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C(C)(C)O[SiH2]C(C)(C)C)cs2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiazol-2-ylamine (CAS [752241-92-2]; WO2004076420) in accordance with the general method of Example 78, step 2 yielded the title compound as an off-white solid, MS (ISP): m/e=457.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)[C:13]2=[O:27])=[CH:4][C:5]2[CH2:10][O:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:28]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[O:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[CH2:21][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2([C:3]3=[CH:4][C:5]4[CH2:10][O:9][CH2:8][O:7][C:6]=4[CH:11]=[C:2]3[O:1][CH2:28]2)[C:13]1=[O:27]
Reactant: O=C1C(c2cc3c(cc2O)OCOC3)c2ccccc2N1C[C@H]1CCCO1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)COCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one was obtained (3%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.38-6.99 (m, 4H), 6.47 (s, 1H), 6.30 (d, J=3.6 Hz, 1H), 5.15 (ABq, 2H), 4.89 (d, J=9.0 Hz, 1H), 4.71-4.61 (m, 3H), 4.30-4.20 (m, 1H), 3.96-3.64 (m, 4H), 2.10-1.60 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 177.8, 160.5, 160.5, 153.9, 142.8, 142.7, 132.3, 132.2, 128.8 (2C), 123.6, 123.3, 122.4, 122.3, 119.6 (2C), 113.9, 109.6, 109.5, 99.2, 91.2, 80.3, 76.9, 68.2, 68.1, 66.2, 57.5 (2C), 44.7, 44.6, 29.2, 29.0, 25.6, 25.5; MS (ES+) m/z 379.9 (M+1), 401.8 (M+23).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])=[O:9])C.[OH-].[Na+].Cl>CCO>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([S:8]([NH:7][CH2:6][CH2:5][C:4]([OH:19])=[O:3])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(S(=O)(=O)NCCC(=O)O)c1
Reaction time: 8 h

Procedure:
To a solution of 3-(3-methoxy-benzenesulfonylamino)-propionic acid ethyl ester (5.62 g), prepared as described in Step F, in 200 mL of EtOH at room temperature was added 1N NaOH (20.54 mL). After stirring overnight, 1 N HCl solution was added until pH <5. The reaction was concentrated in vacuo to remove the EtOH, the residue partitioned between EtOAc and water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25]O)[C:18]=2[O:17]1>>[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)[C:18]=2[O:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Product: CC1(C)Cc2cccc(COc3ccnn3-c3cc(C#N)ccn3)c2O1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,2-dimethyl-3H-1-benzofuran-7-yl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.48 (6H, s), 3.03 (2H, s), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.83 (1H, q, J=8.0 Hz), 7.13 (1H, d, J=7.2 Hz), 7.18 (1H, d, J=8.0 Hz), 7.37 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.07 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H18N4O2, 347. Found, 347.
Reaction SMILES: [C:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:8]=[CH:7][C:6]=1[NH:17][C:29](=[O:30])[CH:28]([N:20]1[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[N:23]=[C:19]1[CH3:18])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To a solution of 5-tert-butyl-1-(4-fluorophenyl)pyrazol-4-amine (0.03 g, 0.13 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.029 g, 0.13 mmol), followed by diisopropylethylamine (0.033 g, 0.26 mmol) and HATU (0.054 g, 0.14 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.0145 g, 0.034 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.45 (q, J=1.2 Hz, 1H), 7.33-7.24 (m, 2H), 7.16-7.07 (m, 2H), 6.89 (s, 1H), 4.90 (d, J=7.3 Hz, 1H), 2.47 (s, 3H), 1.86 (d, J=7.3 Hz, 3H), 1.11-1.03 (m, 9H); MS: (ES) m/z calculated for C21H23F4N5O [M+H]+ 438.2, found 438.0.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH2:18]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCNCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCNCCCN

Procedure:
Approximately 360 g of N-oleyl-1,3-propylenediamine (commercially obtained as Armak Duomeen O) and 150 g of toluene were charged to a 2 liter reactor equipped with heater, agitator, Dean-Stark tube and condenser with provision for blanketing the vapor space with nitrogen. Slowly, over a period of about 10 minutes, approximately 52 g of 88% formic acid were added with agitation. The reaction mixture was slowly heated to about 160° C. over a period of about 5 hours until water removal by azeotropic distillation ceased. The solvent was removed by vacuum distillation at about 160° C. and the mixture was cooled to about 60° C.
Reaction SMILES: C([NH:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15]([NH2:17])=[O:16])[NH:12]1)=[O:10])C1C=CC=CC=1>C(O)(=O)C.CO.[Pd]>[NH:12]1[C@H:13]([C:15]([NH2:17])=[O:16])[CH2:14][C@@H:11]1[C:9]([NH2:8])=[O:10]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)NCc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)[C@@H]1C[C@H](C(N)=O)N1
Reaction time: 8 h

Procedure:
45.8 mg (196 μmol) of cis-N-benzylazetidine-2,4-dicarboxamide in 10 ml of glacial acetic acid (no reaction occurs in methanol) are hydrogenated in a Parr shaker over 11 mg of 10% Pd/C under a hydrogen pressure of 4 atm for 7 hours. The mixture is filtered through a fluted filter and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo yields a colorless film which crystallizes slowly on addition of a few drops of methanol. After standing in a freezer overnight, the crystals are isolated, washed with a small volume of ethyl acetate/methanol (5:1), and dried in vacuo; yield 16.7 mg (60%). Mp. 215°-218° C. (dec.) after strong shrinking and darkening from approx. 200° C. on (measured with oil bath preheated to 190° C.). 1H NMR (D2O): δ 4.29 (t, 2H, J=8.5), 2.98 (dt, 1H, J=9 (t), 11 (d)), 2.23 (dt, 1H, J=8 (t), 11.5 (d)). IR (nujol): 3391, 3335, 3208, 3073, 1683, 1669, 1281, 1211, 1109, 1030, 843, 749, 722, 677 cm-1. Mass Spectrum: CI(isobutane): m/z 144 (M+H, 100%), 99 (56).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.Cl.Cl.[N:25]1([C@@H:30]2[CH2:35][CH2:34][NH:33][C@@H:32]([CH2:36][OH:37])[CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:33]2[CH2:34][CH2:35][C@@H:30]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:31][C@@H:32]2[CH2:36][OH:37])=[O:22])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Reactant: OC[C@H]1C[C@H](N2CCCC2)CCN1
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CC[C@@H](N2CCCC2)C[C@@H]1CO

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and trans-(4-pyrrolidin-1-yl-piperidin-2-yl)-methanol dihydrochloride (example 193B) in direct analogy to the general procedure used in example 150. MS: 477.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([CH:25]3[CH2:27][CH2:26]3)[O:17][C:15]=2[CH:16]=1)(C)(C)C.[ClH:33].O1CCOCC1>C(Cl)Cl>[CH:25]1([CH:18]2[C:19]3=[CH:20][N:21]=[CH:22][CH:23]=[C:24]3[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][C@@H:8]([NH2:7])[CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:16][C:15]=3[O:17]2)[CH2:27][CH2:26]1.[ClH:33]
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC(C1CC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(C1CC1)c1cnccc1-2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl((2S)-1-((5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (250 mg, 0.570 mmol) in CH2Cl2 (4 mL) cooled to 0° C. was added 1N HCl in dioxane (2 mL, 0.570 mmol) slowly over a period of 5 min. The reaction mixture was stirred at 0° C. for 5 min then was warmed to room temperature and allowed to stir for 2 h. The solvents were removed by concentration under reduced pressure. The crude product was washed with ethyl acetate to yield (2S)-1-(5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-amine as an HCl salt (240 mg, 42% yield). LCMS (ESI) m/e 339.2 [(M+H)+, calcd for C21H27N2O2 339.2]; LC/MS retention time (Method C): tR=1.28 min. The diastereomeric mixture of amines was resolved by chiral preparative HPLC (0.2% DEA in n-hexane, ethanol).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(OC)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and (6-methoxypyridin-3-yl)boronic acid (from Aldrich). LCMS calculated for C22H23N4O3(M+H)+: m/z=391.2. Found: m/z=391.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[N:10][CH:11]=[C:12]([CH:14]=[CH2:15])[CH:13]=2)[N:3]=1.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[N:10][CH:11]=[C:12]([C@@H:14]3[CH2:15][C@H:18]3[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=2)[N:3]=1
Reactant: C=Cc1cnnc(-n2nc(C)nc2C)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cnnc(-n2nc(C)nc2C)c1

Procedure:
A solution of 3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-vinylpyridazine (23-3, 530 mg, 2.64 mmol 1.0 eq.) in toluene (35 mL) was refluxed under nitrogen. To the reaction mixture was added ethyl diazoacetate (0.50 mL, 4.75 mmol, 1.8 eq.) dropwise. The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (20% acetone in hexanes) to afford ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropanecarboxylate (23-4) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (d, 1H, J=2.0 Hz), 7.71 (d, 1H, J=2.0 Hz), 4.21 (q, 2H, J=7.2 Hz), 2.93 (s, 3H), 2.56 (m, 1H), 2.43 (s, 3H), 2.16 (m, 1H), 1.82 (m, 1H), 1.51 (m, 1H), 1.30 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>CC(O)(C)C>[CH2:17]([O:16][C:8]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1C=CCCC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C(=O)OCC)[C@@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of Ru[(S,S)-Tsdpen](p-cymene), 194 μL (2.0 mmol) of 2-cyclohexenone, 304 μL (2.0 mmol) of diethyl malonate, and 2 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 409 mg (80% yield) of the title compound. After this was converted into an ethylene ketal derivative as shown in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 61% ee.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=S)[C:11]([C:20]([O:22]CC)=O)=[N:10]2)=[CH:4][CH:3]=1.[NH2:25][NH2:26]>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:25][NH:26][C:20](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=S
Solvent: CCO
Product: O=c1[nH]nc2c3cccnc3n(Cc3ccc(Br)nc3)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (120 mg, 0.296 mmol) was suspended in ethanol (15 mL), treated with hydrazine (1.00 mL, 31.9 mmol, 107 equiv) and placed into an oil bath preheated to 80° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[CH3:20][N:21]([CH3:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][N:12]([C:29](=[O:30])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]([CH3:32])[CH3:20])[CH2:13]2
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: COc1ccccc1C1(O)CC(C)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1C1(O)CC(C)CC2CN(C(=O)Cc3ccccc3N(C)C)CC21
Temperature: 5 °C
Yield: 71.4 %

Procedure:
To a solution of 0.78 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol in 80 cm3 of dichloromethane is added 0.5 cm3 of triethylamine. The reaction mixture is cooled to 5° C. and 0.54 g of (2-dimethylaminophenyl)acetic acid, 0.05 g of 1-hydroxybenzotriazole monohydrate and 0.63 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is maintained for 1 hour at 5° C. and for 16 hours at 20° C. and is then washed twice with 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.060-0.200 mm, diameter 4 cm, height 50 cm), eluting under a pressure of 0.7 bar with a mixture of dichloromethane and methanol [97.5/2.5 by volume] and collecting 65 cm3 fractions. Fractions 17 to 23 are concentrated and, after drying at 40° C. at 15 Pa, 0.90 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-6-methyl-4-perhydroisoindolol is obtained in the form of a white powder which is dissolved in 50 cm3 of dioxane. 3 cm3 of 5M hydrochloric acid solution in dioxane are added and, after 1 hour at room temperature, the solution is concentrated under reduced pressure (2.7 kPa), triturated in isopropyl ether, filtered and dried at 40° C. at 15 Pa. 1.0 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-6-methyl-4-perhydroisoindolol hydrochloride is obtained.