Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:19]3[CH2:25][CH:24]4[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[NH:4].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCOCC1>[CH3:27][N:26]1[CH:21]2[CH2:22][CH2:23][CH:24]1[CH2:25][CH:19]([N:9]1[C:8]3[CH:7]=[CH:6][C:5]([C:3]4[NH:4][C:28](=[O:29])[O:1][N:2]=4)=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1C2CCC1CC(N1c3ccccc3Oc3cc(C(=N)NO)ccc31)C2
Solvent: C1COCCO1
Product: CN1C2CCC1CC(N1c3ccccc3Oc3cc(-c4noc(=O)[nH]4)ccc31)C2
Temperature: 110 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
To a solution of N-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxamidine, 1 h (0.66 g; 1.81 mmol) in dioxane (20 mL) was added 1,1′-carbonyldiimidazole (0.44 g; 2.71 mmol), and the mixture was stirred at 110° C. for 4 h. The mixture was allowed to cool to rt, and the solvent was evaporated. The residue was purified via reverse phase HPLC (eluent gradient: 20 to 45% CH3CN in H2O containing 0.1% TFA) to yield 161 mg (17.6%) of title compound 3-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 2h as a TFA salt. MS m/z (MH+) 390.9.
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[CH3:31][CH:30]([NH:33][C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:24])([F:25])[F:26])[CH:20]=3)[O:15][C:14]([CH3:27])([CH3:28])[C@H:13]2[OH:29])=[N:6][S:7](=[O:9])(=[O:10])[N:8]=1)[CH3:32]
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Reactant: CC(C)N
Product: CC(C)NC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O

Procedure:
In a method similar to Example 5, the product of Example 1, Step 2 (0.200 g, 0.457 mmol) was converted to the title compound with isopropylamine (0.64 mL, 7.5 mmol) in 1 hour to give 0.180 g (87%) of a white solid: mp 296-298 (dec); 1H NMR (DMSO-D6): δ 8.90 (br s, 1H), 8.30 (br s, 1H), 7.26 (s, 1H), 7.23 (d, 1H), 6.91 (d, 1H), 6.00 (d, 1H), 4.78 (d, 1H), 3.86 (br t, 1H), 3.63 (dd, 1H), 1.40 (s, 3H), 1.24 (dd, 6H), 1.16 (s, 3H); IR (KBr) 3300, 1620 cm-1 ; MS (m/z) 451 (MH+, 100%); [α]D25 =-73.5 (THF)
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.30 g, 1.09 mmol) was dissolved in toluene (5 mL). Isopropyl isocyanate (0.93 g, 1.09 mmol) was added and the reaction mixture was stirred at 60° C. for 2 h. Upon cooling to room temperature a precipitation formed which was filtered off and washed twice with dichloromethane. After drying the title compound was obtained as a white solid (330 mg, 85%); MS: m/e=276.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: C=CC(=O)O
Reactant: Nc1ccccc1F
Solvent: CC#N
Product: O=C(O)CCNc1ccccc1F

Procedure:
To a solution of 2-fluoroaniline (2.0 g) in acetonitrile (20 ml), acrylic acid (1.4 ml) was added and heated under reflux for 21 hours. After the reaction mixture was concentrated, the residue was diluted with 10% aqueous sodium hydroxide and washed with chloroform. The aqueous layer was adjusted to pH 3.3 by addition of 12M aqueous hydrochloric acid, and the precipitated crystal was collected by filtration and dried to give N-(2-fluorophenyl)-β-alanine (1.35 g) as a light-yellow solid. N-(2-Fluorophenyl)-(3-alanine thus obtained (1.30 g) was added to polyphosphoric acid (20g) heated at 130° C., followed by stirring for 2.5 hours. After addition of ice-cold water, the reaction mixture was adjusted to pH 5 with 8M aqueous sodium hydroxide. The precipitated crystal was collected by filtration to give 8-fluoro-2,3-dihydroquinolin-4(1H)-one (770 mg) as a yellow solid. To a solution of 8-fluoro-2,3-dihydroquinolin-4(1H)-one thus obtained (700 mg) in trifluoroacetic acid (20 ml), triethylsilane (4.1 ml) was added and stirred at room temperature for 2 hours. Triethylsilane (2.1 ml) was further added and stirred overnight at room temperature. After the reaction mixture was concentrated, the residue was diluted with 1M aqueous sodium hydroxide and extracted with diethyl ether. To the organic layer, 6M aqueous hydrochloric acid was added and stirred to separate the aqueous layer. The aqueous layer was alkalized with 8M aqueous sodium hydroxide and extracted with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1) to give the titled compound, i.e., 8-fluoro-1,2,3,4-tetrahydroquinoline (427 mg) as a light-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cc1cncc(Br)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methyl-benzoic acid ethyl ester and 3-bromo-5-methyl-pyridine
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31](#[N:35])[CH2:32][CH2:33][CH3:34]>C(#N)C>[OH:21][C@@H:19]([C:8]1[N:7]([C@H:4]2[CH2:5][CH2:6][N:2]([CH2:34][CH2:33][CH2:32][C:31]#[N:35])[CH2:3]2)[C:11]2=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=[C:10]2[N:9]=1)[CH3:20]
Reactant: CCCC#N
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCN(CCCC#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-pyrrolidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.046 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) in acetonitrile (0.2 mL) was added butanenitrile, 4-bromo- (5.1 μL, 0.051 mmol). The resulting mixture was stirred at rt for 4 h. The mixture was diluted and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.3 mg (38%) of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(-c2ccccn2)n[nH]1
Solvent: CC#N
Product: Cc1[nH]nc(-c2ccccn2)c1Cl
Temperature: 70 °C
Reaction time: 14 h
Yield: 53 %

Procedure:
Preparation 2: A solution of 2-(5-methyl-1H-pyrazol-3-yl)pyridine (500 mg, 3.15 mmol) in acetonitrile (912 mL) was treated with N-chlorosuccinimide in 6 portions and the resulting mixture stirred at 70° C. for 14 h. The mixture was cooled and then concentrated in vacuo to yield a residue. The residue was partitioned between EtOAc (8 mL) and H2O (3 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to yield a residue. The residue was purified by flash chromatography on silica gel using 20-80% EtOAc in hexanes to give the title compound (300 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:40])[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:20]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(O)(C)(C)C>[C:30]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=[C:28]([C:27]2[C:26](=[O:40])[C:25]([C:21]3[CH:20]=[C:19]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:24]=[CH:23][CH:22]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH:29]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=C(Cc1cccc(-c2ccccc2)c1)Cc1cccc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1C(c2cccc(-c3ccccc3)c2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a degassed solution of 2.84 g of 4,4′-dibromobenzil (7.73 mmol) and 2.80 g of 1,3-di(biphenyl-3-yl)propan-2-one (7, 7.73 mmol) in 30 ml of tert-butanol was added, at 80° C., a methanolic tetrabutylammonium hydroxide solution (1 M, 2.84 ml, 2.84 mmol). The reaction solution was stirred at 80° C. for 20 minutes and then stopped by adding water. Extraction was effected three times with dichloromethane, and the collected organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate before the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: hexane with 20% DCM) and gave 2.85 g of the tetraarylcyclopentadienone 8a as a violet wax (53%, 4.10 mmol). Elemental analysis measured: C 70.5; H 3.3% (calculated for C41H26Br2O: C, 70.9; H, 3.8%); 1H NMR (700 MHz, d8-THF) δ=7.51-7.49 (m, 4H, CH), 7.49-7.46 (m, 4H, CH), 7.41 (dd, J=8.2, 1.1 Hz, 4H, CH), 7.36 (t, J=7.8 Hz, 4H, CH), 7.32 (t, J=8.0 Hz, 2H, CH), 7.29-7.25 (m, 2H, CH), 7.25-7.22 (m, 2H, CH), 7.01-6.99 (m, 4H, CH); 13C NMR (175 MHz, d8-THF) δ=154.28, 141.92, 141.83, 133.58, 132.72, 132.34, 132.30, 132.12, 129.99, 129.89, 129.71, 129.53, 128.26, 127.80, 127.21, 126.74, 123.92; MS (FD, 8 kV): m/z (%): 693.8 (100) [M+] (calculated for C41H26Br2O: 694.0); Rf (hexane with 6% ethyl acetate)=0.47.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[F:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][O:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>C(Cl)Cl>[F:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][O:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:18]=[CH:17][C:13]=1[C:14]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:15]
Reactant: COCCN
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)c(F)c5)cn34)ccnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-ethyl-N-isopropylpropan-2-amine (0.077 ml, 0.44 mmol) and 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoyl chloride-HCl (0.088 g, 0.18 mmol) in DCM (1.25 mL) was added 2-methoxyethanamine (0.023 ml, 0.26 mmol) dropwise. The solution was stirred at room temperature for 5 h. The crude material was concentrated and then triturated with sodium bicarbonate and washed with water. The resultant solid was dissolved in DCM/MeOH and concentrated. The crude material was dissolved in DCM/MeOH and was purified via flash chromatography, eluting with 0-10% MeOH/NH4OH in DCM to yield 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: COCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
1.1 g (0.015 mol) of 2-methoxyethanol was dissolved in 50 ml THF. To this solution 1.5 g (0.03 mol, 50% oil dispersion) NaH, (0.015 mol) 2-(3-chloromethylphenoxymethyl)quinoline hydrochloride, was added slowly. After the addition was completed, the mixture was heated at 70° C. bath temperature for overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gave light yellow oil (1.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[N:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](NC(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl>C(#N)C.O1CCOCC1>[O:15]=[C:12]1[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[N:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][N:24]=3)[CH:18]=2)[N:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
143 mg (0.26 mmol of tert-butyl 4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)piperazine-1-carbamate are dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxane are added. The reaction mixture is stirred at room temperature for 1 h and evaporated. The residue is taken up in water and ethyl acetate, and the water phase is adjusted to pH 12 using NaOH and extracted with ethyl acetate and dichloromethane. The organic phases are combined, dried over sodium sulfate and purified by means of column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])(=O)=O)=CC=1.C1(C)C=CC=CC=1>CN(C=O)C>[F:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:38][C:36]1[CH:37]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[N:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCOCCOCCF)c1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (30 mg, 60 μmol) in DMF (7.6 mL) was added cesium carbonate (44.7 mg, 140 μmol) and 2-[2-(2-fluoroethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (25 mg, 80 μmol) while stirring at room temperature. After 5 hours toluene was added and the mixture was concentrated in vacuum. The DMF free residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate) to yield 16.7 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[OH-].[K+].Br[CH2:18][CH2:19][CH3:20]>C(O)CCC>[CH2:18]([O:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCOc1ccccc1C(=O)CCC(=O)O

Procedure:
3-(o-Hydroxybenzoyl)propionic acid (14.6 g.) was dissolved in n-butanol (300 ml.) containing 85% potassium hydroxide (10 g.) and the resultant solution was treated with 1-bromopropane (24.6 g.) and the mixture heated at reflux temperature for 4 hours. It was then cooled, filtered to remove potassium bromide and the filtrate washed with cold water. The butanol was evaporated at reduced pressure and the residual oil distilled at 0.3 mm when the fraction b.p. 160°-180° C was collected (16.4 g.). This was dissolved in methanol (50 ml.), treated with 20% sodium hydroxide solution (20 ml.) and heated on the steambath for 30 minutes. The methanol was boiled off and the residue diluted with water (250 ml.) and acidified with hydrochloric acid. The precipitated acid was collected and crystallised from 50% methanol. It had m.p. 77°-79° C (Yield 13.3 g.).
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[CH3:11][N:12]([CH3:37])[C:13]([C:15]1[N:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[C:24]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:36])[CH2:34][OH:35])[CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=1)=[O:14]>C(#N)C.[Cu]I>[F:1][CH:2]([F:10])[O:35][CH2:34][C@@H:33]([O:32][C:30]1[CH:29]=[C:24]([CH:23]=[C:22]([O:21][C:18]2[CH:17]=[N:16][C:15]([C:13](=[O:14])[N:12]([CH3:11])[CH3:37])=[CH:20][N:19]=2)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])[CH3:36]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO)c1
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Yield: 62 %

Procedure:
2,2-Difluoro-2-fluorosulfonyl-acetic acid (CAS no. 1717-59-5) (0.84 mL, 8.05 mmol) in acetonitrile (20 mL) was added with a syringe pump dropwise over 90 minutes to a degassed stirring mixture of methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-hydroxypropan-2-yl]oxy-benzoate (1.5 g, 22.0 mmol) and copper (I) iodide (154 mg, 4.55 mmol) in acetonitrile (300 mL) at 55° C. The volatiles were removed under reduced pressure and the residue taken up in DCM. The mixture was filtered to and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 25%-100% ethyl acetate in isohexane to afford the product (16.5 g, 62%). 1H NMR δ (CDCl3): 1.38 (3H, d), 3.15 (3H, s), 3.18 (3H, s), 3.91 (3H, s), 3.93-4.05 (2H, m), 4.62-4.68 (1H, m), 6.27 (1H, t), 6.95 (1H, t), 7.44-7.45 (1H, m), 7.49-7.51 (1H, m), 8.36 (1H, s), 8.53 (1H, s); m/z 404 (M+H+)
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[C:12]([C@H:14]([OH:18])[CH2:15][C:16]#[N:17])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO.C(Cl)Cl>>[NH2:17][CH2:16][CH2:15][C@H:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=1)[OH:18]
Reactant: N#CC[C@@H](O)c1cccc(OC2CCCCC2)n1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(OC2CCCCC2)n1

Procedure:
Reduction of (R)-3-(6-(cyclohexyloxy)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 6 gave after flash chromatography purification (15%-25% 7N NH3/MeOH—CH2Cl2 gradient) Example 26 as a colorless oil. Yield (0.4 g, 33%); 1H NMR (400 MHz, CD3OD) δ 7.61 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 5.05-4.96 (m, 1H), 4.40-4.28 (m, 1H), 2.84 (t, J=6.8 Hz, 2H), 2.08-1.74 (m, 6H), 1.62-1.32 (m, 6H); RP-HPLC tR=7.04 min; ESI-MS m/z 251.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[CH2:15][N:16]=[CH:17][CH:18]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7](=[O:19])[CH2:6]1)=O.[Li+].[BH4-].C(OCC)(=O)C.Cl>CO>[OH:2][CH2:3][CH:5]1[C:14]2[CH2:15][N:16]=[CH:17][CH:18]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7](=[O:19])[CH2:6]1
Reactant: COC(=O)C1CC(=O)c2cccc3c2=C1CN=CC=3
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CC(CO)C2=c3c1cccc3=CC=NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-oxo-1,2,3,4-tetrahydronaphtho[1,8-cd]azepine-3-carboxylic acid methyl ester (70 mg, 0.28 mmol) in MeOH (5 mL) is added LiBH4 (18.3 mg, 0.83 mmol) and the mixture is stirred at RT for 1 h. Ethyl acetate is added followed by ice and 1N HCl. The mixture is washed with brine then water and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by preparative HPLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[C:26]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][NH:9]3)=[CH:4][CH:3]=2)=[O:22])=[C:19]([CH3:18])[N:27]=1
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Reactant: Cc1nc(-c2ccc(F)cc2F)ccc1C(=O)O
Agent: Cl
Product: Cc1nc(-c2ccc(F)cc2F)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (73 mg, 0.30 mmol) and 2-methyl-6-(2,4-difluorophenyl)nicotinic acid (D106) (82 mg, 0.33 mmol) then converted to the HCl salt as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ (ppm): 8.46 (d, 1H), 8.11 (d, 1H), 7.93-8.01 (m, 2H), 7.81 (d, 1H), 7.40 (d, 1H), 7.25 (m, 2H), 3.55 (m, 2H), 2.96 (t, 2H), 2.88 (s, 3H), 2.18 (m, 2H).