Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>O>[C:1]([CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C[C@H](O)CC#N
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a 3-necked jacketed 3 L flask equipped with a mechanical stirrer and connected to an automatic titrater by a pH electrode and a feeding tube for addition of base, was charged H20 (1200 mL), NaCN (37.25 g) and NaH2PO4 (125 g) to bring the solution to pH 7. The water circulator was set to 40° C. After 10 minutes, halohydrin dehalogenase SEQ ID NO: 32 as cell lysate (250 mL) was added. The reaction mixture was allowed to stir for 5 minutes. Using an addition funnel, ethyl(S)-4-chloro-3-hydroxybutyrate (45 g) was slowly added over 1 hour. The pH was maintained at 7 by the automatic titrater by the addition of 10 M NaOH (27 mL) over 17 hours. Subsequently, gas chromatography of a reaction sample showed complete conversion to product. Celite (16 g) was added to the flask, which was then connected to a diaphragm pump, whose exhaust is bubbled into 5M NaOH (200 mL), to remove HCN. The mixture was heated to 60° C. under 100 mm Hg pressure. After 1 hour, a submerged air bubbler was added to the solution to aid the removal of the HCN. After 3 hours, an HCN detector indicated less than 5 ppm HCN in the off-gas. The mixture was allowed to cool to room temperature, then filtered through a celite pad. The filtrate was extracted with butyl acetate (3×800 mL) and the combined organic layers filtered through a pad of activated charcoal. The solvent was removed under vacuum by rotary evaporation to provide 28.5 g of ethyl(R)-4-cyano-3-hydroxybutyrate. The purity was 98% (w/w) by HPLC and the enantiomeric excess was >99% (by chiral GC, the S enantiomer was undetectable). As used herein, the term “enantiomeric excess” or “e.e.” refers to the absolute difference between the mole or weight fractions of major (F(+)) and minor (F(−)) enantiomers (i.e., |F(+)−F(−)|), where F(+)+F(−)=1. Percent e.e. is 100×|F(+)−F(−)|. Enantiomeric composition can be readily characterized by using the gas chromatography method described in Example 6, above, and using methods that are known in the art.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][CH:8]([O:16][CH3:17])[CH2:9][CH:10]1[S:15][CH2:14][CH2:13][CH2:12][S:11]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([CH3:30])=[C:26]([CH2:28]Cl)[N:27]=2)[CH:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([CH3:30])=[C:26]([CH2:28][C:10]3([CH2:9][CH:8]([O:7][CH3:6])[O:16][CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]3)[N:27]=2)[CH:24]=1
Reactant: COC(CC1SCCCS1)OC
Reactant: Cc1c(CCl)nc2ccc(Cl)cn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CC1(Cc2nc3ccc(Cl)cn3c2C)SCCCS1)OC
Temperature: -30 °C

Procedure:
A solution of n-BuLi in hexanes (1.6 M, 1.4 mL) is added dropwise at −50° C. to a solution of 2-(2,2-dimethoxy-ethyl)-[1,3]dithiane (450 mg, prepared according J. Het. Chem, 1987, 1221) in THF. The mixture is then warmed to −30° C. for 1 hour. After cooling to −50° C., a solution of 6-chloro-2-chloromethyl-3-methyl-imidazo[1,2-a]pyridine (300 mg) in 3 mL of THF is added dropwise; the reaction mixture is then slowly warmed to room temperature. After quenching with aqueous NH4Cl solution, the mixture is extracted with ethyl acetate. The extract is washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue is purified on flash chromatographic column, eluting with 5% MeOH in CH2Cl2, to give 6-Chloro-2-[2-(2,2-dimethoxy-ethyl)-[1,3]dithian-2-ylmethyl]-3-methyl-imidazo[1,2-a]pyridine. 1H NMR (CDCl3, ppm): 7.80 (s, 1H); 7.50(d, 1H); 7.05(d, 1H); 4.80(t, 1H); 3.40(m, 8H); 2.75-3.00(m, 4H); 2.40-2.50(m, 5H); 1.80-2.05(m, 2H). Step 2. Preparation of 6-Chloro-2-[2-(6-fluoro-pyridin-2-yl)-2H-pyrazol-3-ylmethyl]-3-methyl-imidazol[1,2-a]pyridine
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.N1C=CC=CC=1>>[NH:31]1[CH:32]=[N:33][C:29]([NH:28][S:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]([NH:8][CH2:7][C:6]3[CH:21]=[CH:22][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=3)=[O:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:30]1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc[nH]n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Nc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A solution/suspension of 4-(4-trifluoromethyl-benzylcarbamoyl)-benzenesulfonyl chloride (200 mg, 0.5 mmol) in methylene chloride (1.0 mL, 16 mmol) was added portion-wise to a 0° C. solution of 3-amino-1,2,4-triazole (48.9 mg, 0.581 mmol) in pyridine (1.0 mL, 12 mmol). After addition was complete, the ice-bath was removed, and the reaction mixture was warmed to rt. After 16 h, the reaction mixture was diluted with methylene chloride and partitioned with 1 N HCl. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, diluted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was loaded onto Celite and purified on the Isco (12 g cartridge, chloroform to 12% MeOH in chloroform) to afford the title compound (150 mg, 60%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:16]([CH2:17][C:18]([O:20]C)=[O:19])[C:15](=[O:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13]3[CH2:33][CH2:34][C:35](=[O:36])[C:12]2=3)=[CH:7][CH:6]=1)#[N:4].O>O1CCCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[O:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:13]3[CH2:33][CH2:34][C:35](=[O:36])[C:12]2=3)=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous sodium hydroxide solution (1 M, 15.0 mL, 15.0 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetate (example 3, 2.64 g, 5.62 mmol) in tetrahydrofuran (40 mL) and the mixture is stirred at room temperature for 4 h. Water is added and the mixture is extracted three times with ethyl acetate. The aqueous layer is acidified a) with hydrogen chloride and extracted twice with dichloromethane. These organic layers are combined and concentrated. Yield: 1.84 g; ESI mass spectrum [M+H]+=456; Retention time HPLC: 0.84 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OCc3ccccc3)cc2)C1
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
To a mixture of 4-benzyloxy-benzoic acid (0.5 g, 2.191 mmol) and HOBT (326 mg, 2.41 mmol) in dry THF (50 ml) was added EDAC (462 mg, 2.41 mmol). The resulting mixture was stirred for 10 min. followed by addition of a mixture of DIPEA (420 μl, 2.41 mmol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (410 μl, 2.41 mmol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (50 ml) and the resulting mixture was extracted with EtOAc (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:3) as eluent. Pure fractions were collected and evaporated to dryness affording 610 mg (77%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[C:7]([C:26]([F:29])([F:28])[F:27])[CH:6]=[C:5]([CH3:30])[N:4]=1.I[Si](C)(C)C>C(#N)C>[OH:2][C:3]1[C:8]([CH2:9][NH:10][C:11](=[O:25])[C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[C:7]([C:26]([F:28])([F:27])[F:29])[CH:6]=[C:5]([CH3:30])[N:4]=1
Reactant: COc1nc(C)cc(C(F)(F)F)c1CNC(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of N-((2-methoxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-phenoxybenzamide (0.12 g, 0.3 mmol) in anhydrous acetonitrile (20 mL) was added iodotrimethylsilane (200 mg, 1 mmol). Then the mixture was stirred at room temperature for 2 hours. Then the reaction mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give the pure product N-((2-hydroxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-phenoxybenzamide (90 mg, 75%). LRMS (M+H) m/z: calcd 402.12. found 402. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, CD3OD): δ 7.79-7.77 (m, 2H), 7.42-7.37 (m, 2H), 7.18 (t, J=6.3 Hz, 1H), 7.04 (d, J=7.5 Hz, 2H), 6.97 (d, J=7.8 Hz, 2H), 6.40 (s, 1H), 4.57 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: C(C1(C2C=CC=C(OC)C=2)CNC(=O)C1)C1C=CC=CC=1.CO[C:24](=[O:44])[CH2:25][C:26]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1>>[NH2:34][CH2:33][C:29]1[CH:28]=[C:27]([C:26]2([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35][NH:36][C:24](=[O:44])[CH2:25]2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(C#N)c1
Agent: COc1cccc(C2(Cc3ccccc3)CNC(=O)C2)c1
Product: NCc1cccc(C2(Cc3ccccc3)CNC(=O)C2)c1

Procedure:
Prepared in analogy to 4-benzyl-4-(3-methoxy-phenyl)-pyrrolidin-2-one starting from 3-benzyl-3-cyano-3-(3-cyano-phenyl)-propionic acid methyl ester (example 56.2)
Reaction SMILES: [F:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]([NH2:17])[CH:3]=1.O1CCOCC1.Br[C:25]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:28]=[C:27]([NH:37][C:38]2[CH:39]=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[NH2:17][C:4]1[N:5]=[CH:6][C:7]([C:25]2[N:30]=[C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[N:28]=[C:27]([NH:37][C:38]3[CH:39]=[N:40][C:41]4[C:46]([CH:47]=3)=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:26]=2)=[C:2]([F:1])[CH:3]=1
Reactant: Brc1cc(Nc2cnc3ccccc3c2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cc(F)c(-c2cc(Nc3cnc4ccccc4c3)nc(N3CCOCC3)n2)cn1
Temperature: 120 °C
Yield: 26 %

Procedure:
To a solution of 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (prepared as shown in Method 10) in dioxane (1.7 mL, 0.13 mmol), N-(6-bromo-2-morpholinopyrimidin-yl)quinolin-3-amine (20 mg, 0.052 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (11 mg, 0.013 mmol) and 2 M aqueous sodium carbonate solution (0.6 mL, 1.2 mmol) were added under argon. The pressure vessel was sealed and the reaction mixture was heated in a microwave reactor at 120° C. for 15 minutes. The crude product was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to give N-(6-(6-amino-4-fluoropyridin-3-yl)-2-morpholinopyrimidin-4-yl)quinolin-3-amine as yellow powder (14 mg, 26%). LC/MS (m/z): 418.0 (MH+), Rt 2.31 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19]([Cl:24])=[N:20][CH:21]=[CH:22][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:24][C:19]1[C:18]([NH:17][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Reactant: Nc1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(C=C(Nc2cccnc2Cl)c2ccncc2)cc1
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone (5.20 g, 24 mmol) and 3-amino-2-chloropyridine (4.04 g, 31.4 mmol) in toluene (150 ml) was added p-toluenesulfonic acid monohydrate (457 mg. 2.4 mmol) and the reaction mixture was brought to reflux with Dean-Stark removal of the toluene/water azeotrope. After 24 h, toluene was removed in vacuo and the residue was resuspended in ethyl acetate. The precipitate was collected by vacuum filtration to give (2-chloropyridin-3-yl)-[2-(4-fluorophenyl)-1-(pyridin-4-yl)-vinyl]amine (5.0 g) as a tan solid. The filtrate was concentrated in vacuo and purified by flash column chromatography (50%-80% ethyl acetate:hexanes gradient) to give additional 1.50 g of product.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9].[Cl:12][C:13]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([N:23]3[CH:31]([OH:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])=[N:20]2)=[CH:15][CH:14]=1.O>C(Cl)Cl>[C:7]([O:33][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31](=[O:32])[N:23]1[C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[N:22][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:20]=1)(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
Pyridine (24 cc) followed, in the course of 30 minutes, by propionyl chloride (5.5 g) are added successively to a solution of 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (3.2 g) in methylene chloride (160 cc), while the temperature is maintained in the region of 25° C. The mixture is stirred for 3 hours at this temperature and then treated with water (100 cc). The organic phase is separated after settling has occurred, washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized in isopropyl ether and then recrystallized in a mixture of isopropyl ether and ethyl acetate (25:75 by volume). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl propionate (1 g), m.p. 160° C., is thereby obtained.
Reaction SMILES: OO.[C:3]([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([OH:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])=O.[Na+].[Na+].[C:29]([OH:33])([CH3:32])([CH3:31])[CH3:30]>>[C:3]([O:11][CH:12]1[CH2:13][C:14]([CH3:22])([CH3:21])[N:15]([O:20][CH2:30][C:29]([OH:33])([CH3:32])[CH3:31])[C:16]([CH3:18])([CH3:19])[CH2:17]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
A solution of 50% aqueous hydrogen peroxide is added slowly to a mixture of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-60° C. Excess peroxide is decomposed by aqueous sodium sulfite solution. The organic layer is concentrated and the residue is purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:37]>O1CCOCC1>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:37])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:34])([F:36])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Solvent: C1COCCO1
Product: NC(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoic acid (39 mg, 0.08 mmol) in 0.8 mL dioxane was added to NbCl5 (64 mg, 0.238 mmol), followed by 0.95 mL NH3 (0.5M in dioxane). The temperature was slowly raised to 50° C. and stirred for 2 days. The solvents were evaporated and the residue dissolved in CH2Cl2, followed by filtration of the precipitate. The residue was dissolved in CH2Cl2 and washed with brine. The combined organic phases were dried, evaporated and the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford analytically pure product.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1.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.CC(C)([O-])C.[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:1]1([CH:7]2[CH2:10][CH:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([NH:20][C:22]5[CH:23]=[N:24][CH:25]=[N:26][CH:27]=5)[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cncnc1
Reactant: Nc1ccc2nc([C@H]3C[C@@H](N4CCCCC4)C3)sc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ncc(Nc2ccc3nc(C4CC(N5CCCCC5)C4)sc3c2)cn1
Temperature: 145 °C
Reaction time: 2 h

Procedure:
The product of Example 101A (cis-2-(3-piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamine) (50 mg, 0.174 mmole), 5-bromopyrimidine (42 mg, 0.264 mmole), tris(dibenzylideneacetone)dipalladium (0) (6.5 mg, 0.007 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 8.7 mg, 0.014 mmole) and sodium tert-butoxide (23 mg, 0.242 mmole) were charged in a tube and sealed. The tube was placed on high vacuum for 2 hours and refilled with nitrogen. Toluene (2 mL) was added and the reaction vessel was placed in a microwave reactor and heated at 145° C. for 15 minutes. After cooling to room temperature, the mixture was diluted with water and extracted three times with with dichloromethane. The combined organic layers were concentrated and the crude product was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane). The product collected was a mixture of cis and trans isomers. 1H NMR (400 MHz, CDCl3) δ ppm 8.79 (s, 1H) 8.50-8.56 (m, 2H) 7.89 (d, J=8.90 Hz, 1H) 7.58 (d, J=2.15 Hz, 1H) 7.18 (dd, J=8.59, 2.15 Hz, 1H) 5.83 (s, 1H) 3.48-3.63 (m, 1H) 2.73-2.85 (m, 1H) 2.59-2.71 (m, 2H) 2.23-2.39 (m, 6H) 1.54-1.66 (m, 4H) 1.41-1.51 (m, 2H). MS: (M+H)+=366.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:9]1([NH:12][CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: O=C1CCC(O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OC1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.3 %

Procedure:
4-hydroxycyclohexanone (443 mg, 3.88 mmol) was dissolved in 1,2-dichloroethane (20 ml), followed by sequential addition of cyclopropylamine (0.295 ml, 4.27 mmol), NaBH(OAc)3 (1.3 g, 6.21 mmol), and acetic acid (0.2 ml, 3.88 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 10% MeOH/MC (15 ml×4). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 580 mg of yellow solid (96%).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][NH2:55])[CH2:48][CH2:47]1>CN(C=O)C>[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]2)=[O:23])[CH2:48][CH2:47]1
Reactant: NCCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCN2CCOCC2)CC1
Reaction time: 0.17 h

Procedure:
NEt3 (1.8 ml) is added to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.5 g) in DMF (40 ml) and the mixture is stirred for 10 min. TBTU (3.15 g) is added, and after additional 10 min the 3-morpholinopropan-1-amine (0.98 ml) is added. The reaction mixture is stirred over night and the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with satd. aqueous NaHCO3, aqueous citric acid (10%) and brine, dried (MgSO4) and filtered, and the solvent is removed under reduced pressure to give crude tert-butyl 4-(3-morpholinopropylcarbamoyl)piperidine-1-carboxylate (2.3 g). The crude product is used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:13][CH2:14][CH2:15][O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCCBr
Reaction time: 2.5 h
Yield: 60.5 %

Procedure:
7.9 g of the 2,3-difluoro-6-nitrophenol, 50.1 g of 1,2-dibromoethane and 18.7 g of potassium carbonate were added to 80 ml of dimethylformamide and the mixture was stirred for 2.5 hours at from about 80° to 100° C. (bath temperature). The reaction mixture was concentrated to dryness in vacuo and the residue was distributed between ethyl acetate and water. The organic solvent layer was washed with water and was dried, then the solvent was evaporated. The residue was dissolved in benzene and was purified by silica gel column chromatography to provide 7.7 g of 2-(2-bromoethoxy)-3,4-difluoronitrobenzene as light yellow oil.