Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([Cl:33])=[O:32]>N1C=CC=CC=1>[ClH:33].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:32]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)c1cccc(F)c1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 40.2 mg (0.25 mmol) of 3-fluorobenzoyl chloride in 1.0 ml of pyridine is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo, and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 48 mg (73.4% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:20]=[C:19]3[C:15]([C:16](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=1)=[CH:8][C:7]([NH:29]C(=O)OC(C)(C)C)=[CH:6][CH:5]=2.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:29][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])/[C:10]/2=[CH:11]/[C:12]1[CH:20]=[C:19]2[C:15]([C:16](/[CH:21]=[CH:22]/[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Reaction time: 1 h

Procedure:
tert-Butyl(E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)-methyl-ene)indolin-5-ylcarbamate (13 mg, 0.027 mmol) was dissolved into CH2Cl2 (1.0 mL) and then trifluoroacetic acid (0.1 mL) was added and the reaction stirred for 1 hour. The solvent was removed and the residue titurated with ether/EtOAc to give after drying 4.6 mg, 29% of the title compound as an orange powder. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J=5.8 Hz, 2H), 8.31 (d, J=8.7 Hz, 1H), 8.21-8.12 (m, 3H), 7.97 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=16.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H); MS ESI 380.1 [M+H]+, calcd for [C23H17N5O+H]+ 380.15.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:31])([CH3:30])[CH2:25][CH2:26][CH2:27][Mg]Cl>C1COCC1>[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C@@:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([OH:22])[CH2:27][CH2:26][CH2:25][C:24]([F:31])([F:23])[CH3:30])[CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Reactant: CC(F)(F)CCC[Mg]Cl
Solvent: C1CCOC1
Product: CC(F)(F)CCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
A solution of (3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine (100 mg, 0.33 mmol) in THF (2 mL) was cooled to −20° C. and 4,4-difluoropentylmagnesium chloride (˜0.79M in THF, 5.0 mL, 4.0 mmol) was added. The mixture was stirred for 2 h and quenched with sat'd NH4Cl. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed on a roto-evaporator. The crude product was purified using flash chromatography (hexanes/EtOAc). N-Boc-(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol was isolated as an oil (70 mg) MS m/z 454 (M+Na).
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]([C@H:11]1[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:28][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)/C=C/CO[Si](C)(C)C(C)(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of ethyl (2E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-2-enoate (3.27 g, 13.4 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.14 g, 17.5 mmol) in CH2Cl2 (30 mL) was added TFA (0.280 mL, 3.64 mmol) at 0° C. The reaction was stirred at rt overnight. The mixture was quenched with water (50 mL) and extracted with EtOAc (two×50 mL). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified via flash chromatography eluting with 20% EtOAc/heptane to give the title compound as a pale yellow oil (2.61 g, 53 yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.08-7.41 (m, 5H), 4.10 (q, J=7.13 Hz, 2H), 3.42-3.73 (m, 4H), 2.37-2.90 (m, 6H), 1.22 (t, J=7.05 Hz, 3H), 0.84 (s, 9H), 0.00 (d, J=1.26 Hz, 6H).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH2:13]([NH:20][CH2:21]C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:21][CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1

Procedure:
42.8 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 41.3 g (0.25 mol) of N-benzylglycine in 750 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([F:42])([F:41])[F:40])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][CH:16]=3)[C:10]([CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:7]=1.[C:43](Br)(=[O:46])[CH2:44][CH3:45]>CN(C1C=CN=CC=1)C>[CH2:35]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:33])(=[O:34])[NH:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:43](=[O:46])[CH2:44][CH3:45])[CH:3]=[CH:4][C:5]=2[C:39]([F:41])([F:40])[F:42])[N:9]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 67 %

Procedure:
Reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) with propionyl bromide (2 equivalents) in the presence of DMAP (1 equiv) according to the procedure of Example 69 gave a 67% yield of the title compound; homogeneous by TLC in 95:5 CH2Cl2 --MeOH.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Reactant: Oc1n[nH]c2ccccc12
Product: CNc1ccc(Cl)cc1C(=O)n1nc(O)c2ccccc21
Yield: 33.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-5-chloroisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 33.5% yield; m.p. 210°-213° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:27]4[CH:28]=[C:29]([F:33])[CH:30]=[C:31]([F:32])[C:26]=4[F:25])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(F)cc(F)c1F
Yield: 23.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,3,5-trifluorophenylboronic acid (available from Combi-Blocks Inc.; 70 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,3′,5′-trifluoro-biphenyl-2-carboxylic acid (23 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ 13.36 (br s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.28-8.39 (m, 2H), 8.10 (d, J=8.3 Hz, 1H), 7.77 (dd, J=8.4, 1.6 Hz, 1H), 7.54-7.66 (m, 2H), 7.22-7.28 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=C(C#N)[CH:28]=[N:29]C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:28]#[N:29])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: N#Cc1cncc(Br)c1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cncc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 5-Bromo-3-cyanopyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=351.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][CH2:19][C:20]([N:9]2[CH2:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: c1ccc(C2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
A solution of 3-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 4-phenyl-1-(3-phenylazetidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 467 mg of colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[O:9][C:8]([CH3:15])([CH3:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:21]Br.[OH-].[NH4+]>C(O)(=O)C>[Br:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[NH:11][C:10](=[O:13])[O:9][C:8]([CH3:15])([CH3:14])[C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: COc1cccc2c1NC(=O)OC2(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(Br)cc2c1NC(=O)OC2(C)C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a mixture of 8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.1 g, 10.1 mmol), sodium acetate (1.5 g, 18 mmol) in acetic acid (30 mL) was added bromine (0.62 mL, 12 mmol) at ambient temperature. After 30 minutes, the solution was treated with a concentrated ammonium hydroxide solution (50 mL). The precipitate was collected on a filter and washed with water (3×20 mL) to yield 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.7 g, 93%) as off-white solid: MS (ESI) m/z 286, 288 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:12]O>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1ncccc1C(=O)O
Agent: Cl
Product: COC(=O)c1cccnc1N
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The mixture of 138 mg of 2-aminonicotinic acid and 6 mL of hydrochloric acid-methanol solution was stirred overnight in a sealed-tube at 90° C. The reaction mixture was concentrated under reduced pressure, the residue was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure, to obtain 106 mg of 2-aminonicotinic acid methylester [25-1]. The obtained compound [25-1] was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[ClH:11].CCOCC.Cl.[Cl:18]N1C(=O)CCC1=O>CCOCC.Cl.C(O)(=O)C>[ClH:18].[Cl:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cnccc1C
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)CCl
Yield: 83.2 %

Procedure:
In a 500 mL round bottom flask was placed 1-(4-methyl-3-pyridinyl)ethanone (10.0 g, 74.1 mmol) in 90 mL of Et2O. To this solution was added 88.9 mL of 1M HCl/Et2O (1.2 eq, 88.9 mmol) with stirring and the solution allowed to stir for 1 h at room temperature, at which point, the precipitate was filtered and washed with Et2O. The solid was then dried in vacuo at about 60° C. This HCl salt (12. g, 70.0 mmol) was then dissolved in 70.0 mL of 1M HCl/acetic acid where 9.34 g (1 eq, 70.0 mmol) of N-chlorosuccinimide (NCS) was added and the reaction allowed to stir under Argon at room temperature overnight. At this point, 300 mL of Et2O was added resulting in an off-white precipitate. This was allowed to stir for 1 h at which point the solid was filtered and rinsed with Et2O to provide 12.0 g (83%) of the desired 2-chloro-1-(4-methyl-3-pyridinyl)ethanone hydrochloride. 1H-NMR (DMSO-d6) δ 2.51 (s, 3H), 5.15 (s, 2H), 7.68 (d, 1H), 8.68 (d, 1H), 9.06 (s, 1H); MS GC-MS [MH]+169.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([NH:9][C:10]([N:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=3)[CH2:13]1)=[O:11])[CH2:2]2.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.CC(O)=O.CO>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C@@H:14]2[CH2:15][CH2:16][N:12]([C:10]([NH:9][CH:3]3[CH2:4][CH:5]4[N:8]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:1]([CH2:7][CH2:6]4)[CH2:2]3)=[O:11])[CH2:13]2)=[N:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4)C2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CS(=O)(=O)N1C2CCC1CC(NC(=O)N1CC[C@@H](Nc3ccc(C#N)cn3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a stirred solution of (3R)—N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamide (18 mg, 0.053 mmol) and i-Pr2NEt (0.075 mL, 0.4 mmol) in CH2Cl2 (1 mL) was added methanesulfonyl chloride (0.008 mL, 0.10 mmol). The mixture was stirred overnight at rt, diluted with HOAc (0.1 mL) and MeOH (0.9 mL) and purified by prep HPLC to afford the title compound (13 mg, 58%). LC-MS Method 1 tR=1.1 min, m/z=419; 1H NMR (CD3OD) [selected resonances] 2.93 (s, 3H), 4.47 (m, 1H), 6.78 (d, 1H), 7.77 (d, 1H), 8.40 (s, 1H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.[F:26][C@H:27]1[C@H:31](OS(C)(=O)=O)[CH2:30][N:29]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[F:26][C@H:27]1[C@@H:31]([O:25][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[C:15]([C:12]2[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=2)[CH:24]=[CH:23]3)[CH2:30][N:29]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:28]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CS(=O)(=O)O[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@H]5CN(C(=O)OCc6ccccc6)C[C@H]5F)c4n3)cnc2c1
Temperature: 100 °C

Procedure:
2-(7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (1.75 g, 5.22 mmol), (trans)-benzyl 3-fluoro-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (1.99 g, 6.3 mmol) and cesium carbonate (3.40 g, 10.4 mmol) were added to a sealed tube containing dimethylacetamide and heated to 100° C. overnight with stirring. The dimethylacetamide was removed under vacuum concentration and heat, chloroform was added, and this organic phase was gently washed with water. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel using a 6% solution of ammonium hydroxide in methanol and dichloromethane to yield three major products which could not be separated further by column purification (starting quinoline phenol, product and unidentified by-product). MS APCI (+) m/z 557.3 (M+1) detected. This crude material was taken directly on to the deprotection step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
(S)-(1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (260 mg, 0.55 mmol), triethylamine (111 mg, 1.1 mmol), and benzoyl chloride (93 mg, 0.66 mmol) were dissolved in dichloromethane (2 ml) and stirred overnight. The reaction mixture was then poured on HCl (1N), and extracted with dichloromethane. The organic layer was washed with NaHCO3 (1N), dried, and evaporated. (S)-(5-Benzoyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester was obtained in sufficient purity for the next step.
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[F:9][C:10]1[CH:15]=[C:14](F)[C:13]([Cl:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>CS(C)=O>[F:9][C:10]1[CH:15]=[C:14]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[C:13]([Cl:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCC(F)(F)F)cc1F

Procedure:
22.5 g of 88% potassium hydroxide are suspended in 120 ml of dimethyl sulfoxide. With stirring, 40 g of trifluoroethanol are added dropwise to this suspension. Then, also with stirring, the resultant solution is added dropwise at room temperature to a solution of 96.8 g of 2,4-difluoro-5-chloronitrobenzene in 150 ml of dimethyl sulfoxide. When the addition is complete, the reaction mixture is stirred for a further 2 hours at room temperature. The reaction mixture is then concentrated, the crude product is dissolved in methylene chloride, and the resultant solution is washed with water and dried. Finally, the solvent is distilled off. Purification is effected by chromatography through a column of silica gel with a 10:1 mixture of hexane and ether as eluant. The solvent is distilled off, affording the title compound of the formula ##STR10## in the form of yellow crystals; m.p.: 54°-55° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[OH:24][CH2:25][CH2:26][NH2:27]>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:27][CH2:26][CH2:25][OH:24])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccc(OC)cc23)cc1

Procedure:
A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.2 g, 0.60 mmol), and 2-hydroxylethylamine (1.5ml) was microwaved at 120° C. for 20 min. The excess of 2-hydroxylamine evaporated under reduced pressure. The product was isolated by preparative TLC (CH2CL2/MeOH=5/3 as eluent) yielded 35 mg (18%). 1H NMR (DMSO): δ 7.2 (d, 2H), 7.1 (d, 2H), 7.05 (d, 1H), 6.9 (d, 2H), 6.2 (s, 1H), 3.75 (s, 3H), 3.5 (t, 2H), 3.4 (t, 2H), 3.41 (s, 3H), 3.2 (s, 3H).
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CC#N>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[NH:1][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:11])[N:18]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CC#N
Product: CCOC(=O)c1[nH]c(-c2ccc(Cl)cc2)nc1C
Yield: 40.8 %

Procedure:
A solution of ethyl 2-oximinoacetoacetate (6 g, 38 mmol; obtained according to Org.Synth. 1941, 21, 67) in MeCN (75 mL) was treated with 4-chlorobenzylamine (5.6 g, 40 mmol) at reflux for 18 h. Next, the reaction mixture was allowed to cool and the yellow solid formed was collected by filtration to give ethyl 2-(4-chlorophenyl)-5-methyl-3H-imidazole-4-carboxylate as a white solid (4.1 g, 40%): mp 237°-238° C.; 1H NMR (300 MHz, DMSO--d6) δ (DMSO) 7.96 (d, J=8, 2H, arom), 7.57 (d, J=8, 2H, arom), 4.27 (q, J=7, 2H, OCH2), 2.54 (s, 3H, Me-imidazole), 1.33 (t, J=7, 3H, OCH2CH3). Analysis calculated for C13H13ClN2O2 : C 58.99; H 4.95; N 10.58. Found: C 59.20; H 4.95; N 10.59.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13]C(C)(C)C)=[O:12])=[O:7])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[CH:19]=[CH:18][C:10]=2[C:11]([OH:13])=[O:12])=[O:7])=[CH:32][CH:33]=1
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccc(F)cc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(/C=C/c2ccc(C(=O)O)c(NC(=O)c3ccc(F)cc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(4-fluorobenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 45 mg of 2-(4-fluorobenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic acid as white solid.