Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1/C=C(\C)/C(O)=O>CC(C)=O>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(Cl)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Agent: C/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC(C)=O
Product: C/C(=C\C1=C(Cl)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 43a was prepared from 42a (0.872 g, 2.84 mmol) as described above for 39a to give 0.121 g (0.437 mmol, 16%) of the product as a yellow solid following flash chromatography (2:3 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes. (0.121 g E; 0.115 g Z methyl ester)
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>COCCOC>[Cl:3][C:2]1[N:1]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: COCCOC
Product: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Cyanuric chloride (3.63 g, 19.7 mmol) was dissolved in ethylene glycol dimethyl ether (50 ml), cooled to -10° C.-0° C. and gradually added dropwise with morpholine (7.00 ml, 80.3 mmol) dissolved in ethylene glycol dimethyl ether (27 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using dichloromethane and ethyl acetate (8:2) as eluant, to obtain 5.13 g (yield: 91.2%) of 2-chloro-4,6-dimorpholino-1,3,5-triazine as colorless crystals having melting point of 173.5° C.-174° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=N[CH:7]=1.Br[C:18]1C=CC(F)=CN=1>>[C:5]1([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:18]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: c1ccc(-n2cnc3cnccc32)cc1

Procedure:
Intermediate 2 was prepared in a manner analogous to Intermediate 1, substituting 2-bromobenzene for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C12H9N3, 197.07; m/z found 198.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.COC1C=C(C=C(C2C=CC(OC3C=CC(C=O)=CC=3)=CC=2)C(O)=O)C=C(OC)C=1.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.[BH4-].[Na+]>C(O)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][OH:30])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: COS(=O)(=O)OC
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(3,5-dimethoxy-phenyl)-2-[4-(4-formylphenoxy)-phenyl]-acrylic acid methyl ester (21) was first prepared by converting the corresponding free acid (3) to the methyl ester by addition of DMF, K2CO3 and dimethyl sulfate in a manner analogous to Example 1 (f) above. Sodium borohydride (0.125 g, 3.3 mmol) was added to a suspension of 21 (1.26 g, 3 mmol) in ethanol (20 mL) and stirred at room temperature for 1 hr. The reaction was quenched with 5% aqueous HCl, and ethanol was evaporated under reduced pressure. Residue was taken up in ethyl acetate (50 mL) and washed with brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexanes-ethyl acetate (1:1). Yield: 1.14 g, 95.0%. Analysis: 1HNMR (DMSO-d6): δ 7.72 (s, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.41 (t, J=2.4 Hz, 1H), 6.28 (d, J=2.4 Hz, 2H), 5.18 (t, J=6.4 Hz, 1H), 4.49 (d, J=4.8 Hz, 2H), 3.72 (s, 3H), 3.57 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[CH2:11][O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O:25][C@@H:26]([C@@H:29]([C@@H:34]([C@H:39]([CH3:44])[O:40][C:41](=[O:43])[CH3:42])[O:35][C:36](=[O:38])[CH3:37])[O:30][C:31](=[O:33])[CH3:32])[CH:27]=O)(=O)C.B(F)(F)F.CCOCC.O>ClCCCl>[C:41]([O:40][C@H:39]1[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:26]([CH3:27])[O:25][C@H:44]1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[CH2:11][O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:43])[CH3:42]
Reactant: CCOC(=O)COCc1cccc(-c2ccccc2O)c1
Reactant: CC(=O)O[C@H]([C@H](OC(C)=O)[C@H](C)OC(C)=O)[C@@H](C=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)COCc1cccc(-c2ccccc2O[C@@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
Part C: Ethyl 3-(2-hydroxyphenyl)benzyloxyacetate (0.85 g, 2.97 mmol) was dissolved in 1,2-dichloroethane (25 ml) in a dry 50 ml flask. L-Fucose tetraacetate (1.97 g, 5.94 mmol) was added in one portion, then boron trifluoride etherate (1.86 ml, 14.84 mmol) was added slowly. The mixture was stirred under nitrogen overnight at room temperature then mixed with water (50 ml). The organic material was separated and the aqueous portion was extracted with dichloromethane (3×5 ml). The extracts were combined with the original organic fraction, dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution hexane to 3:1 hexane/ethyl acetate) which provided 1.0 g (61%) of ethyl 3-(2-(2,3,4-tri-O acetyl-α-L-fucopyranosyloxy)phenyl)benzyloxyacetate.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:65])([C:58]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:65])([F:52])[C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: COC(O)C(F)(F)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (500 mg, 0,92 mmol) from Step C in THF (7.2 mL) was stirred at rt for 30 min. A 0.5 M toluene solution of potassium bis(trimethylsilyl)amide (1.8 mL, 0.90 mmol) was added over 3 min., giving an orange suspension. After 30 min., crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol (95 mg, 0.46 mmol) was added in THF (1.0 mL). After an additional 30 min, the mixture was quenched by the addition of saturated aq. NH4Cl (2 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (75 mL), and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were washed in succession with saturated aq. brine (25 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ether in hexane to give 117 mg of the title compound as a 95:5 mixture of cis and trans isomers, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1cc(C(=O)O)nn1-c1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-3-carboxylic acid (2.1 g), 5-amino-2-neopentyloxybenzonitrile (2.0 g), triethylamine (2.9 g) and diethyl cyanophosphate (2.3 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (1.9 g), melting point: 146–147° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([CH3:18])[CH:11]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:18])[CH:11]=1
Reactant: COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CBr)cc1C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CBr)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50ml round-bottom flask equipped with a magnetic stir-bar, an addition funnel and N2inlet was added 4-(Bromomethyl)-5-[2-(4-methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (468mg, 1.0mmoles, 1eq) and dry CH2Cl2(15ml, 0.1M). The mixture was cooled to −78° C. (dry ice/acetone) after which boron tribromide (1M in CH2Cl2, 3ml, 3.0mmoles, 3eq) was added dropwise over the course of 15minutes. After the addition was complete, the cold bath was removed and the reaction was allowed to warm to room temperature and stirred for 1hour. After this time, the reaction was cooled to 0° C. and quenched very carefully with water. Once the reaction was quenched, it was transferred to a separatory funnel where the phases were separated. The aqueous fraction washed three times with CH2Cl2and the combined organic fractions were dried over Na2SO4, filtered, concentrated in vacuo to yield a quantitative yield of the titled phenol. The product was used without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:44]4[CH2:45][CH2:46][CH:41]([O:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)[CH2:42][CH2:43]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: c1cc(OC2CCNCC2)ccn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(Oc5ccncc5)CC4)c3)n2)n1
Yield: 50.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 4-(piperidin-4-yloxy)-pyridine [CAS-no. 224178-65-8] (0.365 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 50%) as a white foam. MS (ISP) 631.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1([C:41]2[CH:59]=[CH:58][CH:57]=[CH:56][C:42]=2[CH2:43][CH2:44][O:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])[CH2:7][CH2:6][N:5]([C:8]([C@:10]2([O:31][C:32]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[S:34][CH:33]=3)[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:27])[C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[C@@H:11]2[CH2:28][CH2:29][CH3:30])=[O:9])[CH2:4][CH2:3]1>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:41]2[CH:59]=[CH:58][CH:57]=[CH:56][C:42]=2[CH2:43][CH2:44][O:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:3][CH2:4][N:5]([C:8]([C@:10]2([O:31][C:32]3[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[S:34][CH:33]=3)[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:27])[C:17]3[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=3)[C@@H:11]2[CH2:28][CH2:29][CH3:30])=[O:9])[CH2:6][CH2:7]1
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(O)(c2ccccc2CCOCCCC(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(O)(c2ccccc2CCOCCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Silica gel (230-400 mesh, 88 mg) was added to tert-butyl 4-(2-(4-hydroxy-1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)phenethoxy)butanoate (15 mg, 0.018 mmol) in toluene (0.5 mL) and heated to reflux with vigorous stirring for 6 h. Additional silica gel (44 mg) and toluene (0.5 mL) were added and reflux was continued for 18 h. The reaction mixture was cooled to room temperature and the silica gel was removed by filtration through Celite washing with methylene chloride/methanol (1:1, 10 mL) and methanol (10 mL). The solvent was removed under reduced pressure and the residue purified by silica gel chromatography (methanol/methylene chloride) to provide A63 (9.8 mg, 70% yield) as a white solid after lyophilization from water/acetonitrile: 1H NMR (300 MHz, CDCl3) 8.81 (d, J=4.8 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.49 (dd, J=8.0, 5.0 Hz, 1H), 7.23-7.05 (m, 3H), 6.71 (d, J=7.5 Hz, 1H), 6.68 (d, J=1.8 Hz, 0.7H), 6.54 (d, J=1.8 Hz, 0.3H), 5.57-5.40 (m, 1H), 4.93-4.73 (m, 1H), 4.70-4.45 (m, 2H), 3.95-3.01 (m, 9H), 2.81 (dt, J=14.1, 3.67 Hz, 1H), 2.59-1.24 (m, 18H), 1.08-0.96 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:21][O:22][C:23](=[O:40])[CH2:24][CH:25]1[CH2:30][CH2:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C:28]4[CH2:29][CH2:30][CH:25]([CH2:24][C:23]([O:22][CH3:21])=[O:40])[CH2:26][CH:27]=4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ncnc2c1C(=O)N(c1ccc(I)cc1)CCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)CC1CC=C(c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1

Procedure:
A stirred solution of 4-amino-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (40 mg, 0.10 mmol), methyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]acetate (38 mg, 0.14 mmol), cesium carbonate (42 mg, 0.28 mmol) and palladium tetrakis(triphenyl-phosphine) (6 mg, 0.005 mmol) in 1,2-dimethoxyethane (1.0 mL) was heated at 100° C. for 18 hours. The reaction mixture was cooled, concentrated and chromatographed to afford a white solid, 19 mg. IC50 84.3 nM.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]([CH2:14][O:15][C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[CH:18][CH:17]=2)[O:11][C:10]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.CN(C)C=O.[C].[Pd]>[C:1]([N:9]1[CH2:13][CH:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:30][CH:31]=2)[O:11][C:10]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Yield: 7.8 %

Procedure:
A 1.0 g quantity of 10% palladium carbon was added to a solution of 3.8 g of benzyl 4-(3-benzoyl-2-oxooxazolidin-5-yl)methoxybenzoate (compound 120) obtained in Example 5 in 50 ml of acetic acid and 25 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. for 5 hours in a stream of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethanol was added to the obtained residue to collect the crystals by filtration. Thus, 235 mg of the title compound (compound 134) was obtained (yield 8%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1>O>[Br:21][C:22]1[CH:23]=[N:24][C:25]([O:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[N:26][CH:27]=1
Reactant: CCOC(CO)OCC
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ncc(Br)cn1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
2,2-Diethoxyethanol (1.6 g) and cesium carbonate (5.8 g) were added to DMF solution (10 mL) of 5-bromo-2-chloropyrimidine (1.15 g), and stirred at room temperature for 12 hours. After addition of water, the reaction liquid was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (C-200; ethyl acetate:hexane=1:9-1:4) to provide the title compound (1.63 g, 94%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17](C#CC4(C)COC4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.FC1C(B(O)O)=CC=CN=1.C(=O)([O-])[O-].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:23]1[CH2:24][C:20]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:10]3[C:9]2=[CH:8][CH:7]=[CH:12][CH:11]=3)[N:21]=[C:22]1[NH2:25]
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccnc1F
Solvent: CO
Product: NC1=NC2(CO1)c1ccccc1Oc1ncccc12

Procedure:
A vial was charged with (S)-2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (50.0 mg, 0.101 mmol), 2-fluoropyridin-3-ylboronic acid (21.33 mg, 0.151 mmol), potassium carbonate (69.7 mg, 0.505 mmol), and Pd(PPh3)4 (11.66 mg, 10.09 μmol). The vial was flushed with Ar (g), then dioxane (505 μL) and water (0.25 mL) were added in sequence. The vial was sealed and placed in a 70° C. oil for 1 hour. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give a pink solid. The solid was dissolved in MeOH and loaded onto a 500-mg SCX-2 column. The column was first eluted with methanol, then with 2N ammonia in methanol to remove the product. The filtrate was evaporated to give (S)-7-(2-fluoropyridin-3-yl)-3-(3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as pale yellow solid. Found MS: MH+=443.0.
Reaction SMILES: F[C:2]1[C:3]([N+:25]([O-:27])=[O:26])=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([C@@H:15]1[CH2:17][C@@H:16]1[F:18])[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].O.[NH3:29].O.C(Cl)(Cl)Cl>CN(C)C=O>[NH2:29][C:2]1[C:3]([N+:25]([O-:27])=[O:26])=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([C@@H:15]1[CH2:17][C@@H:16]1[F:18])[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)c(N)c([N+](=O)[O-])c2c1=O
Yield: 64 %

Procedure:
Ethyl 6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (13.96 g, 36.14 mmol) was dissolved in dimethyl formamide (180 ml), and 28% ammonia water (60 ml) was added dropwise in while stirring and cooling with ice. After stirring the reaction solution at room temperature for 64 hours, water (100 ml) was added to the reaction solution and then concentrated under a reduced pressure. The water-containing residue obtained was then subjected to extraction with ethyl acetate (100 ml×3), and the organic layers were then combined, washed with water (150 ml×3) and saturated saline solution (200 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the residue obtained was applied to a silica gel chromatography, and 8.92 g (64%) of the title compound was obtained in the form of a pale red, oily substance from a chloroform:methanol=30:1 eluate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[CH:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[CH:25]1([CH2:31][C:32]([NH:34][C:35](=[S:36])[NH:24][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]5[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(CC1CCCCC1)N=C=S
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: C1CCOC1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)CC4CCCCC4)cc3F)c2s1
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To a suspension of 219 (50 mg, 0.145 mmol) in THF (1.5 mL) was added 2-cyclohexylacetyl isothiocyanate (40 mg, 0.22 mmol) [P. A. S. Smith and R. O. Kan. J. Org. Chem., 1964, 2261] and the reaction mixture was stirred for 3 hours transferred onto a flash chromatography column and eluted with EtOAc-MeOH mixture (19:1), to afford title compound 220a (27.5 mg, 31% yield) as a light yellow solid. Characterization of 220a is provided in the table 21.