Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH:20]1([N:19]2[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:16][C:17](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])=[N:18]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/c1cc(-c2ccc(O)cc2)n(C2CCCCC2)n1
Reaction time: 0.5 h
Yield: 122.6 %

Procedure:
To a solution of ester 2.3 (50 mg, 0.120 mmol) in CH2Cl2 (2 ml) at −50° C. was added a 1M solution of BCl3 in CH2Cl2 (600 μl 0.60 mmol), and the mixture was stirred for 30 min at that temperature before being quenched with MeOH, diluted with EtOAc, washed with H2O, saturated NaHCO3 (2×), brine, and dried (Na2SO4). After concentration, the residue was combined with another 0.024 mmol batch for purification by SiO2 chromatography (30% EtOAc/hexanes) to afford 48 mg (100%) of phenol 3.1. MS (ESI) 327.3 (MH+), 325.3 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([O:13][CH3:14])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A suspension of 2.3 g (12.81 mmol) of 6-chloronicotinoyl chloride and 1.53 g (15.37 mmol) of N,O-dimethylhydroxylamine in 46 mL of dichloromethane was cooled to 0° C. After dropwise addition of 5.36 mL (38.4 mmol) of triethylamine the resulting reaction mixture was warmed to RT and stirred for further 16 h. The mixture was subsequently washed with water (40 mL), 5% citric acid (40 mL), water (40 mL), and brine (40 mL). The organic layer was dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 2.30 g. Yield 89%.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH3:21])[C:12]2=[O:29])[CH:5]=1.[OH-].[Li+]>C1COCC1.O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20](=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])[C:12]2=[O:29])[CH3:21])=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc(CN2C(=O)C(=C(C)c3ccc(F)cc3)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=C1C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccc(F)cc1
Reaction time: 12 h
Yield: 31.5 %

Procedure:
A solution of 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (0.33 g, 0.82 mmol) was dissolved in THF 5 ml. Then a solution of lithium hydroxide (0.35 g, 8.2 mmol) in water (2.0 ml) was added. After stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid as yellow powder (100 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3H) 5.06 (s, 2H) 6.08 (d, J=7.83 Hz, 1H) 6.68 (t, J=7.45 Hz, 1H) 6.92 (d, J=7.83 Hz, 1H) 7.11 (t, J=7.45 Hz, 1H) 7.38 (t, J=8.84 Hz, 2H) 7.43-7.51 (m, 1H) 7.46 (dd, J=8.72, 5.68 Hz, 2H) 7.60 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.83 Hz, 1H) 7.92 (s, 1H) 13.03 (s, 1H). MS calcd. for C24H18FNO3 387.4, obsd. (ESI+) [(M+H)+] 388.2.
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[NH2:6][C:7]1[C:8]([CH:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2>N1C=CC=CC=1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:17]2[C:8]3[CH:9]=[CH:10][C:11]4[C:16](=[N:15][CH:14]=[CH:13][CH:12]=4)[C:7]=3[NH:6][S:1](=[O:3])(=[O:2])[N:18]2[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: CN(C)CCNC(c1ccc(F)cc1)c1ccc2cccnc2c1N
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CN(C)CCN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 120 °C
Yield: 18.6 %

Procedure:
Sulfamide (272 mg, 2.84 mmol) was added to a solution of N-[(8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methyl]-N′,N′-dimethyl-ethane-1,2-diamine 415 (160 mg, 0.47 mmol) in pyridine (1.5 ml) and the mixture was heated at 120° C. for 1.5 h in a sealed tube. After cooling, the solvent was removed in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (98:2) to give the title compound (35 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#[N:13])CC[CH2:9]2)=[C:4]([F:14])[CH:3]=1.IC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[C:12]#[N:13])=[C:4]([F:14])[CH:3]=1
Reactant: N#CC1(c2ccc(Br)cc2F)CCC1
Solvent: CI
Product: CC(C#N)c1ccc(Br)cc1F

Procedure:
The title compound was prepared analogously to 1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile in step 2 of example A(236) substituting iodomethane in place of 1,3-dibromopropane. MS (APCI): 253 (M+H+), 255 (M+2+H+).
Reaction SMILES: C([Sn](=O)CCCC)CCC.[O:11]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C@@H:12]1[O:20][C@H:19]([CH2:21][OH:22])[C@H:17]([OH:18])[C@H:15]([OH:16])[C@H:13]1[OH:14].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)Cl.CO.N>O1CCOCC1>[CH2:32]([O:16][C@H:15]1[C@@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@@H:12]([O:11][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C@@H:13]1[OH:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: N
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](OCc3ccccc3)[C@H]2O)cc1
Reaction time: 3 h

Procedure:
Dibutyltin oxide (1.87 g, 7.5 mmol) is added to a solution of p-nitrophenyl β-D-galactopyranoside (1.5 g, 5.0 mmol) in absolute dioxane (40 ml) and the mixture is heated under reflux. After 3 hours, benzyl bromide (3.6 ml, 30 mmol) are added to the solution obtained and the batch is stirred under reflux for a further 48 hours. The solvent is then distilled off in vacuo and the residue is purified by flash chromatography (ethyl acetate/petroleum ether 2:1→1:1]. Colourless crystals (1.58 g 81%) are obtained; TLC [methylene chloride/methanol/ammonia (25%) 15:3:0.2]: Rf=0.69; melting point=127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[CH:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:28])[CH:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: COC(=O)C(N)C(CC(F)(F)F)CC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
4-Chlorophenyl sulphonyl chloride (85 mg, 0.40 mmol) was added to a solution of 2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (108 mg, 0.40 mmol) and pyridine (0.15 mL, 1.00 mmol) in CH2Cl2 (2 mL) and the reaction was subsequently stirred for 18 hours at 25° C. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL). This solution was washed with 1M HCl (2×10 mL) and brine (10 mL), dried over Na2SO4 and evaporated to afford a crude oil which was purified by flash chromatography, eluting with 20:80 EtOAc:hexanes, to provide the title compound (125 mg) as an oil in 70% yield. Mass Spectrum (−ESI): 446.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2Cl)cc1
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2Cl)cc1

Procedure:
Prepared analogous to Example 25 from 4-(2'-chloro4'-fluoro-4-biphenylyl)-4-oxo-butyric acid. Melting point 78°-79° C. (from benzene/petroleum ether 3:2); melting point of the cyclohexylamine salt: 161°-162° C. (from ethyl acetate/methanol 1:1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:36][CH2:37][CH3:38])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:39]1COCC1.[OH-].[K+].S(OC)(OC)(=O)=O>C(OCC)(=O)C.CCCCCC.O>[CH3:39][O:1][C:2]1[C:3]([CH2:36][CH2:37][CH3:38])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)N3CCCC3)c(O)c2CCC)cccc1OCC(=O)OCC
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(=O)N3CCCC3)c(OC)c2CCC)cccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 48 (200 mg, 0.3789 mmol) was added to 2.0 ml of THF then potassium hydroxide (25.5 mg, 0.4546 mmol) was added followed by dimethyl sulfate (71.7 mg, 0.5683 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted three times with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel with 50/50 ethyl acetate/hexane as eluant gave the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:51]=[O:52]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([CH:51]=[O:52])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Reaction time: 0.25 h

Procedure:
To a solution of 0.39 g product of step 2 in 10 ml toluene was dropwise added 1.0 ml of a 1.7 M solution of tert-butyllithium in pentane at −78 C. The resulting orange solution was stirred at −78 C. for 15 min. to the resulting orange solution was added 1.00 ml dimethylformamide at −78 C. The initially read but soon bright yellow solution was stirred at −78 C. for 15 min and was then allowed to thaw to room temperature over 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride, the phases were separated and the organic phase was purified by chromatography on silica gel with dichloromethane:ethyl acetate=19:1. to yield 0.21 g of the title compound as colorless foam (MS: 606.4(M+H+)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@H:9]([NH2:16])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:21]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[NH:16][CH2:18][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C1CCCCC1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-amino-4-(S)-cyclohexyl-butyric acid tert-butyl ester (5 g, 20 mmol) and 4-formyl-5-nitro-2-phenoxypyridine (6 g, 24 mmol) in methylene chloride (100 mL) was stirred at room temperature overnight. NaBH(OAc)3 (0.8 gm, 4 mmol) was added, and the solution was stirred at room temperature for 5 hours. Additional NaBH(OAc)3 (7 g, 33 mmol) was added and the solution was stirred at room temperature for another one hour. The solution was then poured into EtOAc (100 mL). The organic layer washed with aqueous NaCl, dried over MgSO4 and evaporated to yield a residue which was purified by column chromatography (10% EtOAc/Heptane) to yield 4-(S)-cyclohexyl-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyric acid tert-butyl ester as a brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:25](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[CH:25]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)cnc2ccccc12
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCn1cnc2cnc3ccccc3c21

Procedure:
A mixture of N4-[4-(tert-butyldimethylsilanyloxy)butyl]quinoline-3,4-diamine (101 g, 293 mmol) and triethyl orthoformate (43.4 g, 293 mmol) in toluene (200 mL) was heated at reflux for 2 hours and then concentrated under reduced pressure to provide 1-[4-(tert-butyldimethylsilanyloxy)butyl]-1H-imidazo[4,5-c]quinoline as an oil that was used directly in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:11])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.[H-].[Na+]>CN(C=O)C.C(OC(=O)C)C.[Cl-].[Na+].O.O>[Cl:12][C:13]1[N:18]=[C:17]([N:6]2[C@@H:5]([C@@H:3]([CH3:4])[CH:2]([F:1])[F:11])[CH2:9][O:8][C:7]2=[O:10])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: C[C@@H](C(F)F)[C@H]1COC(=O)N1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](C(F)F)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114 mg, 069 mmol) and 2,4-dichloro-5-fluoropyrimidine (115 mg, 0.690 mmol) in DMF (2.26 mL) was added sodium hydride (60% wt.; 35.9 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 10 mL) and ethylacetate (10 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane] to provide (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (134 mg) as a white solid. MS m/z 296.1 (M+H)+; Rt-0.75 min. 1H NMR (400 Mhz, CD3OD) δ ppm 8.69 (d, J=2.6 Hz, 1H), 5.99 (q, J=1.0 Hz, 1H), 5.17 (ddd, J=3.5, 7.4, 8.6 Hz, 1H), 4.69-4.50 (m, 2H), 2.88-2.70 (m, 1H), 1.04 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:52][CH2:51][C:50]([CH3:54])([CH3:53])[CH2:49][C:48]=5[C:55]5[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=5)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH:62]1([NH:65][CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:63]1.C(O)(=O)C.C([BH3-])#N>O1CCCC1>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:48]2[CH2:49][C:50]([CH3:53])([CH3:54])[CH2:51][CH2:52][C:47]=2[CH2:46][N:43]2[CH2:44][CH2:45][N:40]([C:38]3[CH:37]=[CH:36][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][CH:29]([N:65]([CH2:66][CH2:67][C:68]#[N:69])[CH:62]6[CH2:64][CH2:63]6)[CH2:28][CH2:27]5)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:39]=3)[CH2:41][CH2:42]2)=[CH:56][CH:57]=1
Reactant: N#CCCNC1CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC(=O)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC(N(CCC#N)C6CC6)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 340C (240 mg) and 3-(cyclopropylamino)propanenitrile (62 mg) in tetrahydrofuran (10 mL) was added acetic acid (2 mL) and MP-cyanoborohydride (300 mg, 2.15 mmol/g). The mixture was stirred overnight. The mixture was filtered and concentrated under vacuum and the residue was dissolved in dimethylsulfoxide/methanol (1:1, 10 mL) and loaded on Gilson, C18(100A) 250×121.2 mm (10 micron), with 30% acetonitrile to 65% acetonitrile over 40 minutes. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.66 (s, 1H), 8.55 (dd, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.11 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (d, 1H), 6.19 (d, 1H), 4.01 (m, 1H), 3.56 (m, 1H), 3.06 (m, 4H), 2.88 (t, 2H), 2.65 (m, 6H), 2.19 (m, 6H), 2.00 (m, 7H), 1.51 (m, 6H), 0.92 (s, 6H), 0.42 (m, 4H).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Br:18][C:19]1[CH:20]=[C:21]([C:35]([O:37][CH3:38])=[O:36])[CH:22]=[C:23]2[C:28]=1[O:27][C:26](S(CC)(=O)=O)=[CH:25][C:24]2=[O:34]>C(Cl)Cl>[Br:18][C:19]1[CH:20]=[C:21]([C:35]([O:37][CH3:38])=[O:36])[CH:22]=[C:23]2[C:28]=1[O:27][C:26]([N:5]1[CH2:6][CH2:7][O:8][C@H:3]([CH3:2])[CH2:4]1)=[CH:25][C:24]2=[O:34]
Reactant: CCS(=O)(=O)c1cc(=O)c2cc(C(=O)OC)cc(Br)c2o1
Reactant: C[C@@H]1CNCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][NH:12][C:13](=O)[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]([CH2:29][CH3:30])[CH:15]=2)=[O:10])=[CH:7][C:6]=1[CH3:34])([CH3:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C(OCC)C>[CH2:22]([O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([C:13]2[O:10][C:9]([C:8]3[CH:32]=[CH:33][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:34])[CH:7]=3)=[N:11][N:12]=2)=[CH:15][C:16]=1[CH2:29][CH3:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCc1cc(C(=O)NNC(=O)c2ccc(OC(C)C)c(C)c2)cc(C)c1OCc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(-c2nnc(-c3ccc(OC(C)C)c(C)c3)o2)cc(C)c1OCc1ccccc1
Yield: 83.1 %

Procedure:
A solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N'-(4-isopropoxy-3-methyl-benzoyl)-hydrazide (1.57 g, 3.40 mmol) and Burgess reagent (1.06 g, 4.43 mmol) in THF (30 mL) is heated to 110° C. under microwave irradiation for 3 min. The mixture is cooled, diluted with diethyl ether, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-5-(4-isopropoxy-3-methyl-phenyl)-[1,3,4]oxadiazole (1.25 g) as a colourless oil; LC-MS: tR=1.24 min, [M+1]+=443.58.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccnc1COc1nc(N)nc(-c2cc(Br)co2)c1C#N

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 80).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)=[CH:48][C:49]4[N:54]([CH2:55][C:56]#[N:57])[C:53](=[O:58])[CH2:52][O:51][C:50]=4[N:59]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:47]([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)=[CH:48][C:49]4[N:54]([CH2:55][C:56]#[N:57])[C:53](=[O:58])[CH2:52][O:51][C:50]=4[N:59]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)C(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: N#CCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 73.1 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(1-(cyanomethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (6 mg, 0.02 mmol) was reacted to afford the title compound (6 mg, quantitative). LCMS (Method A): RT=3.95 min, M+2H+=412. 1H NMR (500 MHz, MeOD): 7.69 (1H,S), 7.43 (2H, d), 7.38 (2H, d), 7.31-7.30 (3H, m), 7.25-7.24 (m, 2H), 5.13 (2H, s), 5.03 (2H, s), 2.77-2.72 (m, 2H), 2.59-2.53 (m, 2H), 2.26-2.17 (m, 1H), 1.99-1.92 (m, 1H).