Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.Cl.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:22]3[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc(Br)cn2)C1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: F[C@@H]1CCN([C@@H]2CCN(c3ccc(Br)cn3)C2)C1
Temperature: 70 °C
Yield: 38.8 %

Procedure:
Dissolve methanesulfonic acid (S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (3 g, 9.34 mmol) and (R)-3-fluoro-pyrrolidine hydrochloride (1.00 g, 11.21 mmol) in DMF (50 mL) and add Cs2CO3 (9.13 g, 28.02 mmol). Warm to 70° C. overnight. Dilute with dichloromethane (3×40 mL), wash with H2O (50 mL) and brine. Dry with Na2SO4, filter, and concentrate the organic solution. Purify the crude material by chromatography, eluting with 0-50% EtOAc/hexane, to give 1.14 g (39%) of (3R,3′R)-1′-(5-Bromo-pyridin-2-yl)-3-fluoro-[1,3′]bipyrrolidinyl.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:33][O-:34].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:34][CH3:33])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C[O-]
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2,4-dichloro-8-methyl-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1.1 g, 2.15 mmol, Intermediate 40: step d) and dry sodium methoxide (0.58 g, 10.75 mmol) in toluene was heated in a sealed tube at 110° C. for 12 hours, cooled to room temperature, diluted with DCM, stirred for 30 minutes at room temperature and the resulting suspension filtered through Celite® rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (10% MeOH in DCM, gradient) to provide the title compound as a white solid after recrystallization from MeOH and drying under reduced pressure overnight.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1>COCCOCCOC>[CH3:10][N:11]1[CH:15]=[C:14]([NH:16][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:13]=[N:12]1
Reactant: CSc1nccc(=O)[nH]1
Reactant: Cn1cc(N)cn1
Solvent: COCCOCCOC
Product: Cn1cc(Nc2nccc(=O)[nH]2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 2-(methylsulfanyl)pyrimidin-4(3H)-one (5.2 g) obtained in Step A in diethylene glycol dimethyl ether (50 mL) was added 1-methyl-1H-pyrazol-4-amine (4.1 g), the mixture was stirred overnight at 150° C., and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (5.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].NN.[C:15](OCC)(OCC)(OCC)[CH3:16]>C1(C)C(C)=CC=CC=1>[CH3:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]2[O:6][C:15]([CH3:16])=[N:8][N:7]=2)=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ccc(C(=O)NN)cc1O
Agent: NN
Solvent: Cc1ccccc1C
Product: Cc1nnc(-c2ccc(C)c(O)c2)o1
Temperature: 150 °C

Procedure:
A suspension of ethyl 3-hydroxy-4-methylbenzoate (3.60 g, 20 mmol) (from Example 6 supra) in anhydrous hydrazine (10 mL, 318 mmol) (Aldrich) was heated at reflux (150° C. bath temperature) for 3 hours. After cooling to room temperature, mixture was concentrated under reduced pressure to give a dry solid. This was suspended in xylene (50 mL) and concentrated under reduced pressure. Resulting solid was suspended in triethyl ortho-aceate (35 mL, 191 mmol) (Aldrich) and heated at reflux (150° C. bath temperature) for 20 hours with removal of ethanol. After cooling, dichloromethane was added and solid was collected by filtration to give 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol as an off-white crystalline material. (Yield 2.28 g, 60.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:13]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc2c(c1F)CCCC2=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 6-methoxy-1-tetralone (200 mg, 1.1 mmol) in ACN (20 mL) was added Selectfluor (603 mg, 1.7 mmol) at rt, and the reaction was stirred at 40° C. overnight. The reaction was filtered and concentrated. The residue was dissolved in EtOAc (40 mL), filtered, and concentrated. Purification by silica gel chromatography (PE/EtOAc/DCM=20:1:2) gave 90 mg (41%) of the title compound as a yellow solid. [M+H] Calc'd for C11H1FO2, 195. Found, 195.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]#[N:19])=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:20][C:21]1[CH:29]=[C:28]([C:30]([F:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])[CH:27]=[C:26]([CH3:40])[C:22]=1[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[C:21]([CH3:20])=[CH:29][C:28]([C:30]([F:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:36])([F:37])[F:38])=[CH:27][C:26]=2[CH3:40])=[CH:7][C:6]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[N:19]
Reactant: N#Cc1ccc(N)cc1NC(=O)c1ccc(F)cc1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Nc1ccc(C#N)c(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a solution of N-(5-amino-2-cyano-phenyl)-4-fluoro-benzamide (0.20 g, 0.78 mmol) (Example I9) in anhydrous tetrahydrofuran (2.5 ml) under an atmosphere of nitrogen was added at room temperature a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (0.332 g, 1.04 mmol) (Example I4) in anhydrous tetrahydrofuran (2.5 ml). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-[4-cyano-3-(4-fluoro-benzoylamino)-phenyl]-2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide (131 mg, 66% yield). 1H-NMR (CDCl3, 400 MHz): 8.98 (s, 1H), 8.51 (d, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.21 (dd, 1H), 7.84 (m, 2H), 7.68 (d, 1H), 7.34 (s, 1H), 6.78 (t, 2H) ppm.
Reaction SMILES: [I:1]I.[OH:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10]>C1C=CC=CC=1>[OH:3][CH2:4][C:5]1[S:6][C:7]([I:1])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccsc1CO
Reactant: II
Solvent: c1ccccc1
Product: Cc1cc(I)sc1CO

Procedure:
6.58 G. (33 mmol) of mercuric oxide and 7.62 g. (30 mmol) of iodine were added alternately in small amounts to a vigorously stirred solution of 3.84 g. (30 mmol) of 2-hydroxymethyl-3-methylthiophene in 30 ml. of benzene. The reaction was kept at room temperature by cooling with an ice bath. The orange mercuric iodide which precipitated was filtered and washed well with benzene. The combined organic solutions were washed with sodium thiosulfate and saturated sodium chloride solution, dried and evaporated to yield crude 2-hydroxymethyl-3-methyl-5-iodothiophene as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH3:49])[CH:43]=[CH:42][C:41]([CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:41]1[CH:40]=[CH:39][C:38]([CH3:49])=[CH:43][CH:42]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C)cc1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccc(C)cc1
Yield: 67.9 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 12.9 g at a yield of 67.9% in the same manner as in Example 1 except that 12 g (47.8 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 60 ml of THF and 8.41 g (52.5 mmol) of CDI was added; 14.5 g (143 mmol) of diisopropylamine and 60 ml of THF were added and 89.5 ml (143 mmol) of 1.63N BA solution was added dropwise; 23.5 ml (143 mmol) of methyl p-tolylacetate instead of methyl phenylacetate was dissolved in 60 ml of THF; and 48 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 100 g of 4N hydrochloric acid was added, and 240 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 66.2 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (239 mg, 0.8 mmol) was reacted with tert-butyl 3-(5-aminopyridin-2-ylamino)piperidine-1-carboxylate (337 mg, 1.1 mmol) to afford the desired product (300 mg, 69%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:27])C=1.S(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[O:27])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(Sc2cccc(F)c2C#N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cccc(S(=O)c2cccc(F)c2C#N)c1

Procedure:
To a solution of 2 g (7.7 mmol) of 2-fluoro-6-[(3-methoxyphenyl)thio]benzonitrile (Example 13) was added portionwise 1.6 g (9.3 mmol) of m-chloroperbenzoic acid. The resultant mixture was stirred for 24 h. Additional 0.16 g of m-chloroperbenzoic acid was added and the resultant mixture was stirred for 15 min. Excess sodium bisulfite was added, followed by water. The H2O solution was extracted with EtOAc. After drying over MgSO4 and solvent removal, the resultant crude product was purified by flash column chromatography on silica gel with methylene chloride as the eluent. This resulted in 1.7 g of 2-fluoro-6-[(3-methoxyphenyl)sulfinyl]benzonitrile as a solid: mp 103°-111° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OCC)=[O:11]>>[CH2:8]([NH:9][CH:10]=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CCOC=O
Product: O=CNCCc1ccccc1

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-phenylethanamine (1.9 g, 15.70 mmol, 1.00 equiv). This was followed by the addition of ethyl formate (5 g, 67.57 mmol, 4.30 equiv) dropwise with stirring. The resulting solution was stirred overnight at 50° C. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (70:1). This resulted in 2.27 g (97%) of N-phenethylformamide as yellow oil.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1([C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39]C)=[O:38])=[CH:34][CH:35]=3)[NH:30][CH:29]=2)CCCCC1>C(Cl)(Cl)Cl.C1COCC1>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[C:33]([C:37]([OH:39])=[O:38])[CH:32]=2)[CH:28]=[CH:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
Freshly recrystallized pyridinium tribromide (recrystallization from hot AcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuum over KOH) was added in portions (over 10 min.) to a stirring solution of methyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (prepared using procedures describe in WO2004/065367) in CHCl3/THF (1:1, 1.25 L) at 2° C. The reaction solution was stirred at 0-5° C. for 2.5 h, and washed with sat. aq. NaHSO3 (1 L), 1 N HCl (1 L) and brine (1 L). The organic layer was dried (MgSO4) and concentrated. The resulting red oil was diluted with Et2O and concentrated. The resulting pink solid was dissolved into Et2O (200 mL) treated with hexanes (300 mL) and partially concentrated. The solids were collected by filtration and rinsed with hexanes. The mother liquor was concentrated to dryness and the procedure repeated. The solids were combined to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffy pink solid, which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 8.47 (br s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.74 (dd, J=1.4, 8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J=3.7, 11.7 Hz, 1H), 1.98-1.72 (m, 7H), 1.50-1.27 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 168.2, 135.6, 130.2, 123.1, 120.8, 120.3, 118.7, 112.8, 110.7, 52.1, 37.0, 32.2(2), 27.0(2), 26.1. LCMS: m/e 334 (M−H)−, ret time 3.34 min, column A, 4 minute gradient.
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:58])[CH:41]=[C:42]([Cl:57])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1)O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:57][C:42]1[CH:41]=[N+:40]([O-:58])[CH:39]=[C:38]([Cl:37])[C:43]=1[CH2:44][C@H:45]([O:18][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]2[CH:22]=[CH:23][CH:24]=[C:8]([C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:25][C:26]([O:28][C@@H:29]3[CH:34]4[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]4)[CH2:30]3)=[O:27])[CH:9]=2)=[CH:21][CH:20]=1)[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.6 %

Procedure:
To a stirred solution of 4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)-benzoic acid (I17, 243 mg, 0.5 mmol) in DMF (2 mL) was added a solution of (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)-ethanol (172 mg, 0.5 mmol) in DMF (5 mL), followed by DMAP (31 mg, 0.25 mmol) and EDC.HCl (192 mg, 1 mmol). The mixture was allowed to stir at room temperature for 18 h and then the solvent was removed in vacuo. The residue was partitioned between DCM (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic phase was washed with brine (15 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (169 mg, 42%). 1H NMR (400 MHz, DMSO): δ 8.58 (s, 2 H), 8.27 (s, 1 H), 8.02 (d, J=8.1 Hz, 2 H), 7.59 (d, J=8.0 Hz, 2 H), 7.36-7.19 (m, 6 H), 7.10-6.88 (m, 6 H), 6.25 (dd, J=9.5, 4.4 Hz, 1 H), 5.84 (d, J=9.4 Hz, 1 H), 5.20 (s, 2 H), 4.64-4.57 (m, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.67 (dd, J=14.7, 9.7 Hz, 1 H), 3.37 (dd, J=14.1, 4.2 Hz, 1 H), 3.14 (t, J=11.7 Hz, 1 H), 2.83-2.52 (m, 5 H), 1.98-1.90 (m, 1 H), 1.88-1.76 (m, 1 H), 1.69-1.57 (m, 1 H), 1.57-1.44 (m, 1 H), 1.44-1.32 (m, 1 H). LCMS (Method 1): [MH+]=812 at 2.97 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:14][N:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:12]2)[CH:7]=[C:6]([CH3:19])[C:5]=1[C:20]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1>O.C(O)(C)C>[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:14][N:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH2:12]2)[CH:7]=[C:6]([CH3:19])[C:5]=1[C:20]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CN(S(C)(=O)=O)C6)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(OC2CN(S(C)(=O)=O)C2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Aqueous NaOH solution (1 M; 39 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(1-(methylsulfonyl)azetidin-3-yloxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-1, 50 mg) in water (0.5 mL) and isopropanol (0.5 mL) at ambient temperature. The mixture is stirred at ambient temperature for 12 hours. The mixture is concentrated and acidified with 10% aqueous citric acid solution. The resulting mixture is extracted with dichloromethane, and the extract dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:30→0:100) to give the title compound. Yield: 35 mg.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:40]=1[F:49])=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1.Cl>CN(C)C=O>[F:49][C:40]1[CH:41]=[C:42]([O:47][CH3:48])[C:43]([O:45][CH3:46])=[CH:44][C:39]=1[C:25](=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1)[C:24]1[NH:23][C:22](=[O:21])[N:2]([C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:3]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
After adding 240 mg of 2-hydrazinobenzoic acid hydrochloride and 0.295 ml of triethylamine to a solution of 500 mg of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 10 ml of N,N-dimethylformamide (hereinafter, “DMF”), the mixture was stirred at 85° C. for 21 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, dilute hydrochloric acid (pH 3-4) was added and extraction was performed with ethyl acetate. The organic layer was then washed with dilute hydrochloric acid (pH 3-4) and saturated brine, and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (548 mg) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:10][C:9]([F:12])([F:11])[C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[CH:3][CH:4]=1)[OH:13]
Reactant: OB(O)c1cccc(F)c1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Product: O[C@H](c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F

Procedure:
Similar to the above procedure, the title compound was prepared from (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (2) and 3-fluorophenylboronic acid. 1H NMR (CDCl3): δ 7.62 (d, J=6.0 Hz, 2H), 7.56 (d, J=6.3 Hz, 2H), 7.42 (m, 2H), 7.28 (m, 1H), 7.06 (m, 1H), 5.82 (q, J=5.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:29][C:26]1[CH:25]=[C:24]([C:30]#[N:31])[C:23]([C:18]2[CH:17]=[CH:16][C:21]([F:22])=[C:20]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:19]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1cc(F)ccc1-c1ccc(F)c(Br)c1
Product: CC(C)(O)c1ccn2c(-c3cc(-c4ccc(F)cc4C#N)ccc3F)cnc2c1F
Yield: 6 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3′-bromo-4,4′-difluorobiphenyl-2-carbonitrile (prepared in the same way as in Example 2) as described in Example 6 to give 4,4′-difluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile (trifluoroacetate salt) as an off-white solid (23 mg, 6%); m/z (ES+) 408 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:21]OC(=O)C(C)(C)N>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]([CH3:17])([CH3:21])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)N
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl
Product: COC(=O)C(C)(C)N1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 338 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and 2,2-dimethyl glycine methyl ester hydrochloride.