Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[OH:16][C@@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of (2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatographyusing gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (106 mg, 36%).
Reaction SMILES: [CH2:1]([O:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:18]1[C:25]([Cl:26])=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:19]1[N:18]=[C:25]([Cl:26])[N:24]=[C:22]([N:11]2[C:10]([CH3:16])([CH3:17])[CH2:9][CH:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][C:12]2([CH3:15])[CH3:14])[N:21]=1
Reactant: CCCCCCOC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1
Product: CCCCCCOC1CC(C)(C)N(c2nc(Cl)nc(Cl)n2)C(C)(C)C1

Procedure:
62.7 g of 4-hexyloxy-2,2,6,6-tetramethylpiperidine are added with stirring to a solution of 23.9 g of cyanuric chloride in 100 ml of toluene. The mixture is subsequently heated to 80° for 24 hours. A white precipitate of the piperidine hydrochloride is formed during this. After cooling, the precipitate is filtered off, and the toluene solution is washed a number of times using 2N hydrochloric acid, dried over Na2SO4 and evaporated. The residue is recrystallized from acetonitrile. The product obtained melts at 49°-51°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:12]2=[O:13])[CH:2]=1
Reactant: NCCNCc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCCN1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 1.6 g of N-(3-pyridylmethyl)-ethylenediamine dissolved in 30 ml of tetrahydrofuran, 1.49 g of carbonyldiimidazole was added at 0° C. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 4 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=15:1) and recrystallized from a mixture of isopropanol and hexane to give 1.43 g of 1-(3-pyridylmethyl)-2-imidazolidinone.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH2:14][CH:15](O)[CH3:16])=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:63]=[N+:64]=[N-:65])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:63]([CH:15]([CH3:16])[CH2:14][O:13][C:3]1[C:2]([CH3:1])=[C:10]2[N:5]([CH:4]=1)[N:6]=[CH:7][N:8]=[C:9]2[S:11][CH3:12])=[N+:64]=[N-:65]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CSc1ncnn2cc(OCC(C)O)c(C)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1ncnn2cc(OCC(C)N=[N+]=[N-])c(C)c12
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
Procedures given in Tetrahedron Lett, 1977, 1977, and JACS, 1999, 3637 were modified. Thus, a 10 mL flask was charged with 1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (249 mg, 0.98 mmol), and tetrahydrofuran (4.91 mL) and cooled to 0° C. Triphenylphosphine (516 mg, 1.96 mmoles), diethyl azodicarboxylate (310 μL, 1.96 mmol) and diphenylphosphoryl azide (424 μL, 1.96 mmol) were added in order. The mixture was stirred at 23° C. for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give (156 mg, 57%) of 6-(2-azidopropoxy)-5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazine as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J=2.8, 9.6 Hz), 4.05-3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J=6.3 Hz). LCMS m/z 254 (M+H+). B. 6-(2-Azido-propoxy)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine and 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol were reacted together according to the procedure described in Example 7 to afford 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine. The crude material was purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 8.32 (1H, d, J=9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J=3.6 Hz), 4.21 (1H, d, J=7.0 Hz), 4.09-4.02 (2H, m), 2.42 (3H, s), 1.23 (3H, d, J=6.3 Hz). LCMS m/z 382 (M+H+). C. A solution of 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in ethyl acetate (2.0 mL) was stirred in the presence of hydrogen (14 psi) and 10% Pd/C (10 mg) for 12 h. Excess hydrogen was removed and the mixture was filtered through Celite® and evaporated. The residue was purified by preparative HPLC to afford (10 mg, 54%) of the title compound. LCMS: m/z 357 (M+H+). Dihydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 12.19 (1H, s), 8.31 (1H, d, J=8.9 Hz), 8.16 (2H, br. s), 8.05 (1H, m), s), 7.97 (1H, s), 7.60 (1H, s), 6.60 (1H, s), 4.19 (2H, m), 4.03 (2H, m), 3.65 (1H, m), 1.30 (3H, d, J=6.8 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:50])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[CH:34][C:33]([N:36]7[CH2:41][CH2:40][N:39]([CH:42]8[CH2:45][O:44][CH2:43]8)[CH2:38][C@@H:37]7[CH2:46][CH3:47])=[CH:32][N:31]=6)[C:26](=[O:48])[N:25]([CH3:49])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[CH2:46]([C@H:37]1[CH2:38][N:39]([CH:42]2[CH2:43][O:44][CH2:45]2)[CH2:40][CH2:41][N:36]1[C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]2[C:26](=[O:48])[N:25]([CH3:49])[CH:24]=[C:23]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:8]4[CH2:7][CH2:6][N:5]5[C:4]6[CH2:3][C:2]([CH3:50])([CH3:1])[CH2:13][C:12]=6[CH:11]=[C:10]5[C:9]4=[O:14])[C:20]=3[CH2:21][OH:22])[CH:28]=2)=[N:31][CH:32]=1)[CH3:47]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A mixture of 164a (200 mg, 0.30 mmol) and NaBH4 (36 mg, 0.90 mmol) in methanol (30 mL) was stirred at 30° C. for 2 h. The mixture was quenched with water and concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 164 (140 mg, 72%) as light green solid. MS-ESI: [M+H]+ 679.3. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.27 (s, 1H), 6.85 (s, 1H), 6.82 (d, J=9.0 Hz, 1H), 5.06 (s, 1H), 4.71-4.61 (m, 5H), 4.52-4.50 (m, 1H), 4.34-4.32 (m, 1H), 4.16 (d, J=4.5 Hz, 2H), 3.87-3.85 (m, 1H), 3.72 (s, 3H), 3.55-3.50 (m, 1H), 3.33-3.30 (m, 1H), 3.12 (t, J=5.0 Hz, 2H), 2.58-2.55 (m, 3H), 2.52 (s, 2H), 2.44 (d, J=3.5 Hz, 2H), 2.35 (t, J=5.5 Hz, 1H), 1.68-1.64 (m, 1H), 1.42-1.37 (m, 1H), 1.28 (s, 6H), 0.82 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(#N)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:16]1[CH2:17][CH2:18][CH:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:12][N:11]=2)[CH2:14][CH2:15]1
Reactant: Fc1ccc(-c2nnc(C3CCNCC3)o2)cc1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (160 mg, 0.55 mmol) in acetonitrile (15 mL) was added triethylamine (0.192 mL, 1.4 mmol), then methyl 2-bromoacetate (0.066 mL, 0.715 mmol). The mixture was stirred overnight at room temperature for 8 h. The white precipitate was filtered, washed with acetonitrile, then ether. The mother liquor which contained the desired product was evaporated yielding the title compound as a white solid (100 mg) which was used without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 8.03 (dd, J=9.09, 5.05 Hz, 2H) 7.19 (t, J=8.59 Hz, 2H) 3.74 (s, 3H) 3.30 (s, 2H) 2.93-3.10 (m, 3H) 2.35-2.54 (m, 2H) 2.12 (dd, 4H). MS (m/z, MH+): 320.5
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 187 mg (60.1%) of the desired product as a solid.
Reaction SMILES: [NH3:1].[F:2][C:3]1([F:10])[CH2:5][C:4]1([CH3:9])[C:6](Cl)=[O:7]>O1CCOCC1>[F:2][C:3]1([F:10])[CH2:5][C:4]1([C:6]([NH2:1])=[O:7])[CH3:9]
Reactant: N
Reactant: CC1(C(=O)Cl)CC1(F)F
Solvent: C1COCCO1
Product: CC1(C(N)=O)CC1(F)F
Yield: 81 %

Procedure:
Gaseous ammonia is passed for 90 minutes into a stirred solution of 15.45 g (0.1 mol) of 2,2-difluoro-1-methyl-cyclopropane-carbonyl chloride in 80 ml of dioxane at 20° to 30° C. The resultant suspension is then evaporated to dryness under a water pump vacuum. The residue remaining is stirred with 50 ml of water, filtered off with suction and dried. In this manner, 11 g (81% of theory) of 2,2-difluoro-1-methyl-cyclopropyl-carboxamide in form of a solid substance of melting point 125°-127° C. are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26][CH3:27])[C:20]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[C:19]3[Cl:39])([OH:15])[C:13]#[CH:14])[CH2:9]1)=O)(C)(C)C.C(O)=O.Cl>>[NH:8]1[CH2:11][CH:10]([C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26][CH3:27])[C:20]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)=[C:19]3[Cl:39])([OH:15])[C:13]#[CH:14])[CH2:9]1
Reactant: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=CO
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CNC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing tert-butyl 3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidine-1-carboxylate (165 mg, 0.29 mmol, Example 8) was added formic acid (5 mL, 132.5 mmol). The solution was cooled to 0° C. and 6 N aqueous HCl (50 μL, 0.3 mmol) was added. The mixture was stirred at 0° C. for 30 minutes then allowed to warm to room temperature. After 60 minutes, the reaction mixture was quenched with MeOH (10 mL) and stirred for 15 minutes and then concentrated. The residue was passed through a short column of silica gel (5% MeOH-DCM increasing to 10% 2 M NH3 in MeOH) which afforded the title compound as a light amber solid. 1H NMR (400 MHz, CD3OD) δ 8.44 (d, J=2.0 Hz, 1H), 8.01-7.72 (m, 3H), 7.53 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 4.43-4.25 (m, 3H), 4.22-4.09 (m, 2H), 4.06 (d, J=2.2 Hz, 3H), 3.88 (t, J=9.7 Hz, 1H), 3.49-3.36 (m, 1H), 3.36 (d, J=1.9 Hz, 1H). MS (ESI): mass calcd. for C24H20ClF3N2O2, 460.1; m/z found 460.9 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCOCC1.[OH:36][C:37]([CH3:42])([CH3:41])[C:38](=O)[CH3:39].[BH3-]C#N.[Na+]>CO>[CH3:28][O:27][C:25](=[O:26])[C@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][CH:38]([CH3:39])[C:37]([OH:36])([CH3:42])[CH3:41]
Reactant: CC(=O)C(C)(C)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(C)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of TFA-Phe-Leu-OMe (0.56 mmol) in MeOH was added N-methylmorpholine (0.93 mL, pH=7), 3-hydroxy-3-methyl-2-butanone (0.84 mmol), and NaCNBH3 (0.72 mmol) under a N2 atmosphere. The reaction mixture was stirred overnight at room temperature and quenched with 50 mL of saturated NaHCO3. The aqueous layer was extracted 3 times with EtOAc (25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and then flash chromatographed (1-3% MeOH/CH2Cl2 ; SiO2 gel) to yield 0.17 g (80% yield) of N-(2-hydroxy-2-methyl-1-methylpropyl)-L-phenylalanyl-L-leucine methyl ester as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7][C:6]2=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7][C:6]2=[O:17]
Reactant: CCC(=O)N1CCC(=O)c2cc(OC)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A mixture of 6-methoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.957 g) and aluminum chloride (3.359 g) in benzene (42 ml) was heated at 60° to 65° with stirring for 4 hours. To the aluminum chloride complex was added a mixture of crushed ice and 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (30 g) with a mixture of chloroform and methanol (50:1 to 10:1) as an eluent. The eluates were evaporated in vacuo to give 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.52 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C:17](=[O:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 20 h
Yield: 96.5 %

Procedure:
4,4-Dimethyl-3-oxochol-5-en-24-oic acid methyl ester (19.8 g) (G. Aranda et al., Tetrahedron 43 (1987), 4147) is reduced with sodium borohydride (9.9 g) in 1900 ml methanol at room temperature. The solution is stirred for 20 hours. After aqueous work-up, 3β-hydroxy-4,4-dimethylchol-5-en-24-oic acid methyl ester (19.2 g) is isolated. Melting point: 136-138° C. 1H-NMR (CDCl3, 400 MHz): δ=5.55 (1H, m); 3.67 (3H, s); 3.23 (1H, m).
Reaction SMILES: [CH3:1][C@@:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]C(=O)N[C:3]1=[O:8].[OH2:15].N>C(OCC)(=O)C>[NH2:6][C@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[C:3]([OH:15])=[O:8]
Reactant: C[C@@]1(c2ccccc2)NC(=O)NC1=O
Reactant: O
Agent: N
Solvent: CCOC(C)=O
Product: C[C@@](N)(C(=O)O)c1ccccc1
Temperature: 160 °C

Procedure:
22 g (0.115 mol) of (+)-(5S)-5-methyl-5-phenylhydantoin, 100 ml of water and 100 ml of 28% aqueous ammonia are introduced successively into a 1 liter autoclave. The medium is heated at 160° C. for 15 hours. After cooling to room temperature, the solution is concentrated under reduced pressure. The white solid obtained is treated with 100 ml of ethyl acetate for 2 hours and then filtered and dried under vacuum at 80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=O)[CH:21]=[CH:22][CH:23]=1.CNCCNC>N1C=CC=CC=1.C(Cl)Cl.[Cu]I>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][NH:19]2)=[CH:3][CH:4]=1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Agent: [Cu]I
Agent: CNCCNC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2C=CC=CN2)cc1

Procedure:
A solution of the product from Example 34F, 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0.340 mmol), pyridazin-3(2H)-one (52.3 mg, 0.544 mmol), N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and copper(I) iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a nitrogen atmosphere in a sealed vial was heated in an oil bath to 135° C. for 16 hours. The reaction mixture was cooled and diluted with DCM (10 mL), filtered through diatomaceous earth and washed with DCM. The filtrate was washed sequentially with H2O, 28-30% NH4OH (10 mL×2), and H2O, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with concentrated NH4OH/MeOH/DCM (0.4/4/96) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05 (m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d, J=6 Hz, 2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz, 1H). MS (DCl—NH3) m/z 310 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:18])[CH2:10][S:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CCOCC.O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:18])[CH2:10][S:11][C:12]([CH3:16])([CH3:17])[C:13]([O:15][CH3:19])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(SCC(=O)c1cc(F)cc(F)c1)C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)SCC(=O)c1cc(F)cc(F)c1

Procedure:
To a solution of 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]thio}-2-methylpropanoic acid from Step A (400. mg, 1.46 mmol) in MeOH (3 mL), was added trimethylsilyldiazomethane (2 M in hexanes) until yellow color persists. The reaction mixture was stirred for an additional twenty minutes. The reaction mixture was diluted with ether (30 mL) and water (10 mL). The organics were washed with 5% sodium bicarbonate and then with saturated brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:Hexanes-40:60 to 90:10, to give the title compound. MS: m/z=229 (M−CO2Me).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[O:9])[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:42][CH2:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[F:52])=[O:45]>C(N(CC)CC)C.C(Cl)Cl>[F:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:44](=[O:45])[CH2:43][NH:42][C:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:9])[CH2:15][CH2:14]1)=[O:18]
Reactant: NCC(=O)c1ccccc1F
Reactant: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)C1CCN(C(=O)Oc2cccnc2)CC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a mixture of 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (500 mg) and DCM (10 mL) were added HOBt (297 mg) and WSC hydrochloride (498 mg), followed by stirring at room temperature for 30 minutes. Then, 2-amino-1-(2-fluorophenyl)ethanone hydrochloride (417 mg) and triethylamine (0.31 mL) were added thereto, followed by stirring at room temperature overnight. The reaction liquid was purified directly by silica gel column chromatography (chloroform/methanol=99/1 to 95/5) to obtain pyridin-3-yl 4-{[2-(2-fluorophenyl)-2-oxoethyl]carbamoyl}piperidine-1-carboxylate (423 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Reaction time: 0.17 h
Yield: 2.5 %

Procedure:
A solution of 5-[(2-fluorophenyl)amino]-N-piperidin-4-yl-1,3,4-oxadiazole-2-carboxamide (Intermediate 101) (200 mg, 0.66 mmol) and 6-chloronicotinamide (103 mg, 0.66 mmol) in dry DMF (4 mL) was heated in the microwave at 125° C. for 20 minutes and then for a further 10 minutes at 135° C. The mixture was filtered and purified by preparative HPLC to give the title compound (7 mg, 2.5%) as a solid; 1H NMR δ 1.55-1.65 (2H, m), 1.83-1.86 (2H, m), 2.99 (2H, t), 4.04-4.12 (1H, m), 4.42-4.46 (2H, m), 6.87 (1H, d), 7.11 (2H, m), 7.21-7.30 (2H, m), 7.72 (1H, s), 7.94-8.03 (2H, m), 8.62 (1H, d), 8.99 (1H, d), 10.61 (1H, s); MS m/e MH+ 426.