Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:35])[C:5]2[N:10]=[N:9][N:8]([CH:11]3[CH:15]([O:16]C(=O)C4C=CC=CC=4)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([O:32]CC)([O:29]CC)=[O:28])[O:12]3)[C:6]=2[N:7]=1.N1C(C)=CC=CC=1C.C[Si](Br)(C)C.[NH4+].[OH-].C([O-])(O)=O.[Na+]>CC#N>[NH2:1][C:2]1[NH:3][C:4](=[O:35])[C:5]2[N:10]=[N:9][N:8]([CH:11]3[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:29])[OH:32])[CH2:14][CH:15]3[OH:16])[C:6]=2[N:7]=1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2nnc3c(=O)[nH]c(N)nc32)O1)OCC
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: Nc1nc2c(nnn2C2OC(C=CP(=O)(O)O)CC2O)c(=O)[nH]1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Compound 10.1 (390 mg, 0.774 mmol) was dissolved in 15 mL CH3CN, treated with 2,6-lutidine (0.3 mL, 2.59 mmol) and TMSBr (1.5 mL, 11.4 mmol). The mixture was stirred for 2 h and coevaporated with CH3CN under reduced pressure. The residue was treated with NH4OH (10 mL) and stirred at 45° C. for 1.5 h. The mixture was treated with 500 mg NaHCO3 and concentrated down under reduced pressure. The residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to yield compound 10.2 (220 mg, 73% yield). 1H NMR (D2O) δ 2.28 (m, 1H), 2.45 (m, 1H), 4.90 (m, 2H), 5.8 (m, 1H), 6.15 (m, 1H). 31P NMR (D2O) d 18.77. LRMS (ESI) MH+ C10H13N6O6P requires 345.2. Found 345.0.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26](Br)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Nc1ncnc(Br)c1C(=O)Nc1ccc(O)c(F)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3ccc(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.37 mmol), 4-amino-6-bromo-N-(3-fluoro-4-hydroxyphenyl)pyrimidine-5-carboxamide (183 mg, 0.56 mmol), DIEA (325 μl, 1.87 mmol) and cesium fluoride (113 mg, 0.74 mmol) were suspended in tert-butanol (5 ml) and the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 15 mg (8% yield) as a solid. Purity 99%.
Reaction SMILES: Cl.Cl.[F:3][C:4]1([F:20])[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.[C:21]([O:25][C:26]([N:28]([CH:41]([CH3:43])[CH3:42])[CH2:29][C@H:30]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(=O)OCC>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:30]([C:31]([N:16]2[CH2:17][CH2:18][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C:4]([F:3])([F:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:14][CH2:15]2)=[O:32])[CH2:29][N:28]([CH:41]([CH3:42])[CH3:43])[C:26](=[O:27])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:35][CH:36]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CC(F)(F)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(F)F)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a solution of (R)-7,7-difluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.015 g, 0.046 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.016 g, 0.046 mmol), and DIEA (0.024 ml, 0.14 mmol) in 1.7 mL DCM was added HBTU (0.017 g, 0.046 mmol). The reaction mixture was stirred 15 hours, after which 2M Na2CO3 was added. The mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified on silica gel (Biotage 12S) by first flushing with about 120 mL 5:1 DCM:EA, then gradient to 1:1 DCM:EA to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((R)-7,7-difluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.018 g, 68% yield) as a white foam. MS (APCI)+ m/z 578 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1Cl
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1-c1cccnc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VI, and 3-pyridineboronic acid, the desired product is obtained in the form of a white foam (yield=27%).
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH2:18]([C:17]1[N:8]2[C:9]([C:10](=[O:12])[NH:11][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:7]2)=[C:13]([CH2:14][CH3:15])[N:16]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)NC(CC)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(CC)c2c(=O)[nH]c(C3CCCC3)nn12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.65 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]pentanamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]#[N:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: N#Cc1c(N)sc2ccccc12
Product: N#Cc1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12
Yield: 93.1 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-aminobenzo[b]thiophene-3-carbonitrile (4.0 g) and 2,5-difluoronitrobenzene (3.7 g), 2-(4-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (6.7 g) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.[CH3:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=2[N:13]=[C:17]1[C:16]1[CH:20]=[CH:21][N:22]=[CH:23][C:15]=1[CH3:14]
Reactant: CNc1ccc(C(F)(F)F)cc1N
Reactant: Cc1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 120 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
A mixture of 0.38 g of N1-methyl-4-trifluoromethylbenzene-1,2-diamine, 0.33 g of 3-methylisonicotinic acid, 0.46 g of WSC and 10 ml of pyridine was stirred for 5 hours while heating at 120° C. After cooling down to room temperature, water was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue were added a mixture of 0.57 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 1 hour while heating at 80° C., and stirred for 2 hours while heating at 120° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 1-methyl-2-(3-methylpyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 6).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:6][N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)([OH:3])=[O:2].BrN1C(=O)C[CH2:23][C:22]1=O>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:2][C:1]([C:4]1[C:5]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[N:6][N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)=[O:3])[CH3:23]
Reactant: CC(C)(C)n1cc(C(=O)O)c(-c2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)(C)C)nc1-c1ccc(F)cc1
Yield: 75.2 %

Procedure:
Add a solution of NaOH (15%, 6 mL) to a solution of 4-ethoxycarbonyl-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.350 g, 1.2 mmol) in MeOH (3 mL) and then add acetonitrile (1 mL). Stir the mixture at 50° C. for 3 h, cool to RT and add HCl (10%) until the pH=3. Extract the mixture with EtOAc (3×100 mL). Combine the organic layers and wash with brine (100 mL), dry (MgSO4) and concentrate to provide 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole as a yellow solid (0.320 g), MS (ESi+): 229.1 (M+H)+. Next treat a solution of 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.315 g, 1.2 mmol) in DMF (15 mL) previously degassed with N-bromosuccinimide (0.235 g, 1.32 mmol) at RT for about 18 h. Dilute the mixture with EtOAc (80 mL) and wash with cooled water (5×10 mL), dry (MgSO4), and concentrate to provide the desired compound as yellow solid (0.262 g, 73% yield).
Reaction SMILES: CN(C)C(=O)C.C(N(C(C)C)CC)(C)C.Br[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:19][C:18]=1[CH3:32].[CH:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34]>[Cl-].[Na+].O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:32][C:18]1[CH:19]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:21]=[C:22]([CH3:23])[C:17]=1[C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:33]=[O:34])[CH:40]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Under a nitrogen atmosphere, a mixture of palladium chloride (82.8 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (387.7 mg), N,N-dimethylacetamide (500 mL) and diisopropylethylamine (60.4 g) was stirred at 70° C. for 2 hr. To the obtained mixture were added 2-bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (100.0 g) and 3-formylphenylboronic acid (46.7 g), and the mixture was stirred at 70° C. for 1 hr. Deaerated water (450 mL) was added dropwise at 70° C., and the mixture was stirred for 8 hr. The reaction mixture was cooled, 10% brine (200 mL) was added, and the mixture was extracted with toluene (600 mL). The aqueous layer was extracted again with toluene (600 mL). The organic layers were combined, and washed with 10% brine (600 mL) and then water (600 mL). To the organic layer was added activated carbon (10.0 g), and the mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, and washed with toluene (300 mL). The filtrate was concentrated to 300 mL under reduced pressure, to which was added toluene (600 mL), and the mixture was concentrated again to 300 mL. To the concentrated solution was added ethanol (300 mL), and the mixture was stirred at room temperature for 30 min. Normal heptane (1200 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr and at 5° C. for 2 hr. The precipitated solid was collected by filtration, and the solid was washed with a mixture (300 mL) of ethanol*normal heptane (1:4), and dried under reduced pressure to give 2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (96.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH2:18][CH2:19][C:20]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21]4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:6]([CH3:31])[N:5]=[C:4]([C:32]#[N:33])[CH:3]=1.[F:34][C:35]1([F:42])[CH2:38][CH:37]([C:39](O)=[O:40])[CH2:36]1.C1(C(Cl)=O)CCCC1.C1(CC(Cl)=O)CCCC1.C(OC(=O)C)(=O)C.C(Cl)(=O)C(C)(C)C>>[F:34][C:35]1([F:42])[CH2:38][CH:37]([C:39]([N:22]2[CH2:23][CH2:24][C:20]([CH2:19][CH2:18][N:14]3[CH2:13][CH:12]4[CH2:11][N:10]([C:8]([C:7]5[C:2]([CH3:1])=[CH:3][C:4]([C:32]#[N:33])=[N:5][C:6]=5[CH3:31])=[O:9])[CH2:17][CH:16]4[CH2:15]3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:40])[CH2:36]1
Reactant: Cc1cc(C#N)nc(C)c1C(=O)N1CC2CN(CCC3(c4ccccc4)CCNC3)CC2C1
Reactant: O=C(O)C1CC(F)(F)C1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C(Cl)C1CCCC1
Agent: O=C(Cl)CC1CCCC1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C#N)nc(C)c1C(=O)N1CC2CN(CCC3(c4ccccc4)CCN(C(=O)C4CC(F)(F)C4)C3)CC2C1

Procedure:
The following were prepared analogously from 4,6-dimethyl-5-{5-[2-(3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-carbonitrile using the acylating agent in parenthesis in place of 3,3-difluorocyclobutane-carboxylic acid in the final step according to the procedure in step 8 of example 5: III-5 (cyclopentanecarbonyl chloride): III-6 (cyclopentyl-acetyl chloride), III-7 (acetic anhydride) and III-8 (pivaloyl chloride).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@@H:35]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH:40]([CH:37]2[CH2:38][CH2:39][C@@H:35]([N:34]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36]2)[OH:41])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=CC1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
A solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.23 g, 2.83 mmol, Adesis) in THF (10 mL) was cooled to about 78° C. and n-BuLi (1.6 M in hexanes, 2.3 mL, 3.7 mmol) was added drop-wise while keeping the temperature below about −70° C. The mixture was stirred for about 40 min, and a solution of (3R)-3-(dibenzylamino)cyclopentanecarbaldehyde (0.83 g, 2.8 mmol, Step B) in THF (3 mL) was added drop-wise, and the resulting mixture was stirred at about −75° C. for about 2 h. The reaction mixture was quenched by a drop-wise addition of saturated aqueous NH4Cl (20 mL), and the organic solvent was removed under reduced pressure. The aqueous mixture was extracted with EtOAc (25 mL) and the organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in heptane to yield (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol (1.14 g, 67%): LC/MS (Table 2, Method a) Rt=3.31 min; MS m/z: 602 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[C:23]4[C:18](=[C:19]([O:24]C)[N:20]=[CH:21][CH:22]=4)[N:17]([CH3:26])[CH:16]=3)=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[C:23]4[CH:22]=[CH:21][NH:20][C:19](=[O:24])[C:18]=4[N:17]([CH3:26])[CH:16]=3)=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1nccc2c(-c3c(OCC4CC4)ccc4cc[nH]c34)cn(C)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2c(OCC3CC3)ccc3cc[nH]c23)c2cc[nH]c(=O)c21
Temperature: 75 °C
Yield: 7.6 %

Procedure:
A mixture of Example 98C (0.09 g, 0.26 mmol) in dioxane (5.2 mL) was treated with hydrogen chloride (4M in dioxane) (6.5 mL, 26 mmol) and heated at 75° C. for 30 minutes. The reaction mixture was neutralized with saturated sodium bicarbonate solution. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 20% methanol in dichloromethane). The material was further purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-80%) to provide the title compound (0.0066 g, 7.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (d, J=4.88 Hz, 1H), 10.38 (s, 1H), 7.41 (m, 2H), 7.12 (t, J=2.75 Hz, 1H), 6.86 (d, J=8.54 Hz, 1H), 6.80 (dd, J=6.71, 5.80 Hz, 1H), 6.37 (dd, J=3.05, 1.83 Hz, 1H), 6.14 (m, 1H), 4.15 (s, 3H), 3.74 (d, J=6.71 Hz, 2H), 1.03 (m, 1H), 0.40 (ddd, J=8.09, 5.95, 4.27 Hz, 2H), 0.15 (ddd, J=5.95, 4.58, 4.43 Hz, 2H). MS (ESI+) m/z 334.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)C[C@@H]1C[C@H]1CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C[C@@H]1C[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of trans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50 mg, 0.38 mmol), benzyl bromide (0.050 mL, 0.42 mmol), potassium carbonate (58.4 mg, 0.42 mmol) and DMF (2 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give benzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44.0 mg, 0.200 mmol, 52%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:38]=[C:39]([NH:44][C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C:40]([NH2:43])=[CH:41][CH:42]=1>C(Cl)Cl.CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[NH:43][C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]=1[NH:44][C:45]1[N:46]=[CH:47][CH:48]=[CH:49][N:50]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(F)cc1Nc1ncccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (199 mg, 1.05 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (222 mg, 1.15 mmol) and HOAt (143 mg, 1.05 mmol) were added to 4-fluoro-N2-pyrimidin-2-yl-benzene-1,2-diamine (215 mg, 1.05 mmol) in DCM (8.0 ml) and DMF (800 μl) at 0° C. The reaction was stirred for 2 h then poured into water and the aqueous layer extracted with DCM (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% methanol/DCM) to yield the title compound (350 mg, 0.93 mmol, 89%). LCMS: RT 2.98 min [M+H]+ 376.1. 1H NMR (CDCl3, 300 MHz): δ 8.48 (1H, br s), 8.42 (2H, d, J=4.9 Hz), 7.69 (1H, br s), 7.50 (2H, m), 6.84 (1H, td, J 8.5, 2.9 Hz), 6.76 (1H, t, J=4.9 Hz), 5.01 (1H, br s), 4.28 (1H, qn, J=7.6 Hz), 1.44 (9H, s), 1.43 (3H, d, J=7.4 Hz).
Reaction SMILES: Cl.[CH3:2][CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)C>C(O)C.O>[CH3:2][CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH2:7][CH2:6]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: CCC[C@H]1CC[C@@H](N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: O
Product: CCC[C@H]1CC[C@@H](N2CCC(=O)CC2)CC1
Yield: 91.4 %

Procedure:
cis-4-(2-methyl-ethyl)-cyclohexyl-amine hydrochloride(60.7 g) was dissolved in ethanol (725 ml). Potassium carbonate (51.8 g) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (126.6 g) dissolved in water (240 ml) were added and the mixture was refluxed for 1 hour. The reaction mixture was concentrated and extracted three times with dichloromethane. The combined organic layers were washed with aqueous bicarbonate and water, dried (MgSO4) and evaporated. Filtration over silica gel (cyclohexane/ethylacetate 17:3) yielded 69.7 g of a yellow oil which was distilled to yield the title compound (75%) as a slightly yellow oil. b.p. 111° C./0.45 mbar; m/z=223 [M+.].
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[C:8]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:12](=[O:18])[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>C1C=CC=CC=1>[C:26]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[C:8]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:12](=[O:18])[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O:25][CH2:23][CH3:24])=[O:27]
Reactant: CN1CCCCC1=C1c2ccccc2CC(=O)c2sccc21
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCCC1=C1c2ccccc2CC(=O)c2sccc21

Procedure:
Using the procedure of Example IA, react 21.3 g of N-methylpiperidylidene-4H-benzo-[4,5]-cyclohepta-[1,2-b]-thiophene-10(9H)-one in 300 ml of benzene with a solution of 10.9 g of ethylchloroformate in 300 ml benzene to prepare the title compound.