Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=2[N:9]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: CCOC(=O)CBr
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc2c(-c3ccco3)nc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (4 mL) was treated with 4-(N,N-dimethylamino)pyridine (5 mg, 0.04 mmol) and ethyl bromoacetate (55 μL, 0.5 mmol), stirred at room temperature for 16 h and purified directly by chromatography [SiO2; EtOAc:Heptane (1:2)] to give the title compound (50 mg, 35%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:11][C:12]([O:14]C)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:11][C:12]([OH:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of (±)-methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoate (Example 145-C) (254 mg, 0.248 mmol) in MeOH (6 mL) was added 1N NaOH (1.439 mL, 1.439 mmol) and the resulting solution was stirred at rt. After stirring for 1.5 hrs additional 1N NaOH (1.439 mL, 1.439 mmol) was added to the mixture and the mixture was stirred at rt for 16 hrs. At this point, additional 1N NaOH (1.439 mL, 1.439 mmol) was added and the mixture was heated to 60° C. for 3.5 hrs. The reaction mixture was then cooled to rt, diluted with water and the aqueous layer (pH=10) was washed AcOEt (4×). The water layer was acidified with 1N HCl (pH=2-3) and then extracted with AcOEt. The organic layer was washed with water (2×). The combined organic layers were passed through a phase separator and concentrated to give crude product that was purified via preparative HPLC (HC-B) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50-12.64 (m, 1H) 10.92 (br. s., 1H) 7.87-8.25 (m) 7.48 (d) 7.13 (t, J=2.78 Hz, 1H) 6.79 (s, 1H) 5.97 (dd, J=2.91, 1.89 Hz, 1H) 5.34 (dd, J=9.73, 4.67 Hz, 1H) 3.78 (s, 3H) 3.54-3.69 (m, 1H) 2.59-2.65 (m, 1H) 2.44 (s, 3H). HRMS calcd. for C21H18N4O3 (M+H)+ 375.1457. found 375.1458.
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[CH:27]=[CH:28][C:29]2[C:39](=[O:40])[C:38]([C:41]([OH:43])=[O:42])=[CH:37][N:31]3[C@@H:32]([CH3:36])[CH2:33][O:34][C:35]=1[C:30]=23>CS(C)=O>[CH3:36][C@@H:32]1[N:31]2[CH:37]=[C:38]([C:41]([OH:43])=[O:42])[C:39](=[O:40])[C:29]3[CH:28]=[CH:27][C:26]([N:15]4[CH2:16][CH2:17][C@@H:13]([C:10]5([NH:8][CH3:9])[CH2:11][CH2:12]5)[CH2:14]4)=[C:35]([C:30]=32)[O:34][CH2:33]1
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn5c4c3OC[C@@H]5C)C2)CC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (125 mg, 521 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (132 mg, 500 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 20 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding concentrated hydrochloric acid (3 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding water (3 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by recrystallization from ethanol-ammonia water and then dried under a reduced pressure. 135 mg (70%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([F:19])[C:11]=1[F:18])[N:8]([CH3:20])[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]2=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)cc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 10 h
Yield: 77.3 %

Procedure:
A mixture of 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (0.3 g), anhydrous potassium carbonate (0.8 g), methyl iodide (1.6 g), and N,N-dimethyl-formamide (DMF) (10 ml) was heated with stirring at 90°-100° C. for 10 hours. The mixture was evaporated to dryness. The residue was treated with water, extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was added to a mixture of 18% hydrochloric acid (5 ml) and ethanol (2.5 ml) and the mixture was refluxed for 2.5 hours. After water (5 ml) and ethanol (5 ml) added and cooled, the resulting precipitate was filtered off and recrystallized from a mixture of DMF and ethanol to give 6,7,8-trifluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid (0.22 g), mp 255°-258° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)S(O[C:18]1[O:36][CH2:35][C@:21]2([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[N:22]=[C:23]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:24][CH2:25][C@@H:20]2[CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:18]2[O:36][CH2:35][C@:21]3([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[N:22]=[C:23]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:24][CH2:25][C@@H:20]3[CH:19]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)COC(OS(=O)(=O)C(F)(F)F)=C[C@H]2CS1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
(4-Cyanophenyl)boronic acid (55 mg, 0.37 mmol, 2.0 equiv) was added to a solution of (4aR,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4,4a,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-6-yl trifluoromethanesulfonate (P4) (100 mg, 0.19 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL). An aqueous 2 M solution of cesium carbonate (0.47 mL, 0.935 mmol, 5.0 equiv) and dichlorobis(triphenylphosphine)palladium(II) (6.4 mg, 9 μmol, 0.05 equiv) were added. The reaction was de-gassed and stirred at 65° C. for 17 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL) and the organic layer separated. The extraction was repeated twice and the combined organics were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 64 mg, 70%. LCMS m/z 488.3 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[N:39]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[N:39]1([CH:45]2[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][S:5]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:22]5[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=6)[CH:21]=5)[NH:16][N:15]=4)[CH2:10][CH2:9]3)(=[O:7])=[O:6])[CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCC(N5CCCCC5)CC4)CC3)n[nH]c12
Yield: 39.2 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and 4-piperidino-piperidine (187 mg, 1.11 mmol) to afford the title compound (53.14 mg, 39% for 2 steps).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:7]=3[C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C=CC(O)=CC=1)O>O1CCOCC1>[F:28][CH:2]([F:1])[C:3]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]3=[CH:9][CH:10]=2)[N:5]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[N:4]=1
Reactant: COc1ccc2c(c1)CCc1c(C(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Product: COc1ccc2c(ccc3c(C(F)F)nn(-c4ccc(S(N)(=O)=O)cc4)c32)c1
Yield: 84.9 %

Procedure:
4-[3-(Difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (Example 1, Step 2) (600 mg, 1.5 mmol) was dissolved in 1,4-dioxane (200 ml), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (341 mg, 1.5 mmol) was added. The reaction was heated to reflux for 16 hours, at which time a second equivalent of DDQ (340 mg, 1.5 mmol) was added and the reaction was heated to reflux for an additional 24 hours. At three successive 24 hour intervals, 1.5 mmol additional DDQ was added and heating continued until no starting material was left (as determined by thin layer chromatography). The reaction was cooled to room temperature, at which time most of the hydroquinone by-product precipitated. The reaction was filtered and concentrated. The residue was chromatographed on silica gel eluting with 50% ethyl acetate in hexane to yield 4-[3-(difluoromethyl)-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (514 mg, 85%): 1H NMR (acetone d6) δ=3.9 (s, 3H), 7.05 (m, 1H), 7.2 (t, 1H j=54.0 Hz), 7.5 (m, 2H), 7.7 (m, 1H), 7.9 (m, 3H), 8.2 (d, 2H, j=8.7 Hz); 19F NMR (acetone d6) δ-113.3 ppm (d, 2F).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][C:13]3[CH:14]=[C:15]([C:19]4([C:23]([NH2:25])=[O:24])[CH2:22]C[CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.BrCCBr>>[CH3:1][C:2]1[N:3]([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][C:13]3[CH:14]=[C:15]([C:19]4([C:23]([NH2:25])=[O:24])[CH2:22][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCC3)c2)cc1
Solvent: BrCCBr
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CC3)c2)cc1

Procedure:
The titled compound was prepared according to the procedure described for 1-[3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]cyclobutane-1-carboxamide except that 1,2-dibromoethane was used in place of 1,3-dibromopropane (Example 20).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.Cl.[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21][NH2:22].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: NCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C(=O)NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 2.00 g (8.51 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 60 ml of tetrahydrofuran 1.27 g (8.51 mmol) of 3,3,3-trifluoropropylamine hydrochloride, 1.67 g (8.51 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.17 g (8.51 mmol) of 1-hydroxybenzotrizole hydrate and 4.46 ml (25.5 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Silicagel was added and the solvent was removed by distillation. The residue was purified by chromatography on silicagel dichloromethane/methanol 7:3 to yield 2.33 g (94%) of the title compound, MS m/e (%): 258.1 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH:9](O)([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)O
Product: CC(C)Oc1ccc(Br)nc1

Procedure:
The title compound was prepared from 2-bromo-5-hydroxypyridine and isopropanol in analogy to Example 9c): MS (EI): 215 and 217 M+.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([Cl:20])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1OCC(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
A mixture of 2-(2,2-difluoroethyl)oxy-5-nitro-nicotinic acid (310 mg, 1.25 mmol), 2.0 mL thionyl chloride, 5.0 mL DCM and one drop of DMF was refluxed for 4 h and concentrated i.vac. The corresponding acid chloride was directly used for the next step without further purification.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]([OH:9])=O)[C:2]([NH2:4])=[O:3].[CH:10]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:26]4[CH2:31][NH:30][CH2:29][C:27]=4[N:28]=3)=[CH:19][CH:18]=2)=[O:15])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[N:24]=[C:25]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:26]4[CH2:31][N:30]([C:7](=[O:9])[CH2:6][CH2:5][NH:1][C:2]([NH2:4])=[O:3])[CH2:29][C:27]=4[N:28]=3)=[CH:21][CH:22]=2)=[O:15])[CH2:11][CH2:12]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: NC(=O)NCCC(=O)O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)CCNC(N)=O)C2

Procedure:
Method as example 127 using 3-ureidopropanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials to afford a white solid (22.3 mg, 0.044 mmol, 16%.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:15]([OH:28])[CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C:6]1=[O:35])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>CO>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:15]([OH:28])[CH2:16][NH:37][CH3:36])[C:6]1=[O:35])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2c(=O)n(C(C)(C)C)c3ccccc32)cc1
Reactant: CN
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1c(=O)n(C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-one (0.55 g, 1.6 mmol) and para-toluenesulfonyl chloride (0.37 g, 1.9 mmol) in anhydrous pyridine (5 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a cold 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester. To a solution of (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester (0.8 g, 1.6 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (4 mL, 8 mmol) and the reaction mixture stirred for 12 hours at room temperature in a sealed tube. Upon completion, the reaction was partitioned between a saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (silica, 20% MeOH in dichloromethane) to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-methylamino-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour s. The ethanol was removed in vacuo and the clear oil was triturated with diethyl ether/dichloromethane to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride as a white solid. HRMS: calcd for C21H27N3O2+H+, 354.21760. Found (ESI, [M+H]+), 354.2179.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.Cl.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)CCC>[C:18]1([NH:24][N:25]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCC(C(=NNc2ccccc2)c2ccccc2F)CC1
Yield: 82.7 %

Procedure:
A mixture of 14.6 g of 4-(2-fluorobenzoyl)-1-methylpiperidine, 12.0 g of phenylhydrazine hydrochloride and 16.0 g of sodium acetate in 280 ml of n-butanol was heated under reflux for 3.5 hrs. The reaction mixture was cooled, filtered and concentrated. The residue was washed with ether to yield 17 g (83%) of 4-(2-fluorobenzoyl)-1-methylpiperidine phenylhydrazone, mp 131°-134° C.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[NH:31])[NH2:30])[CH2:24]1.CC(C)([O-])C.[K+]>C(O)C>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:3][N:30]=[C:29]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24]2)[N:31]=1
Reactant: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Reactant: CC1CCCN(C(=N)N)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2cnc(N3CCCC(C)C3)nc2-c2ccoc2C)ccn1
Temperature: 25 °C
Yield: 66 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-f uranyl)-2-(2-methyl-4-pyridinyl)-2-propen-1-one (541 mg, 2.000 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (533 mg, 3 mmol) in ethanol (10 ml) was stirred at room temperature. Potassium tert-butoxide (449 mg, 4.00 mmol) was added and the mixture was heated at reflux for 90 minutes. After cooling to room temperature the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in isohexane to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-methyl-4-pyridinyl)pyrimidine as a gum (460 mg, 66%). A solution of 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-methyl-4-pyridinyl)pyrimidine (460 mg, 1.3 mmol) in dichloromethane (2 ml) was treated with hydrogen chloride (1M in diethyl ether, 1.5 ml). The solvent was evaporated and the residue was co-evaporated with diethyl ether (×2). The residue was triturated with diethyl ether and the resulting solid was collected, washed with diethyl ether and dried to give the title compound as a pale yellow solid (450 mg, 89%). LC/MS [M+H]+=349. 1H NMR (400 MHz, d6-DMSO): δ 8.59 (1H, d), 8.54 (1H, s), 7.81 (1H, s), 7.57-7.52 (1H, m), 7.51 (1H, d), 6.02 (1H, d), 4.70-4.60 (2H, m), 3.06-2.98 (1H, m), 2.70-2.77 (1H, m), 2.66 (3H, s), 2.39 (3H, s), 1.84-1.19 (5H, m), 0.93 (3H, d).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[K+].[Br-].S1C2C=CC=CC=2C(N2CCN(CCCCN3C(=O)C[C:32]4([CH2:36][CH2:35][CH2:34][CH2:33]4)C(O)C3=O)CC2)=N1>>[CH2:36]1[C:35]2([CH2:6][C:5](=[O:7])[O:4][C:1](=[O:3])[CH2:2]2)[CH2:34][CH:33]=[CH:32]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Agent: [Br-]
Agent: [K+]
Product: O=C1CC2(CC=CC2)CC(=O)O1

Procedure:
Diacid IVe (10.5 g, 57.0 mmol) was dissolved in acetic anhydride (40.0 g, 0.392 mol) and heated to reflux for 15 h. The excess acetic anhydride was distilled off and the resulting oil taken up in a minimum of hot benzene. Slow dilution with hot hexane afforded 8.90 g (two crops, 95%) of IVf as off-white needles, mp 64-5° C.; IR (KBr) 1800, 1770, 1080, 1065, 955 cm-1 ; 1H NMR (CDCl3) δ 5.68 (s, 2H), 2.78 (s, 4H), 2.34 (s, 4H); mass spectrum, m/z (relative intensity) 167 (M+1, 100), 149 (15), 139 (8), 121 (8), 80 (10).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20][CH2:21][CH3:22])=[N:9]1)C1C=CC=CC=1.C(O)C>[C].[Pd].C(O)=O>[CH2:21]([O:20][C:10]1[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:8][N:9]=1)[CH3:22]
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCC
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)CCc1c[nH]nc1OCC
Yield: 71.9 %

Procedure:
A mixture of ethyl 3-(1-benzyl-3-ethoxy-1H-pyrazol-4-yl)propionate (21.20 g), 5% palladium-carbon (40.00 g), ethanol (200 ml), and formic acid (100 ml) was refluxed for one hour. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (10.70 g, yield: 72%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).