Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2I.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:38])=[CH:35][CH:34]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2/[CH:38]=[CH:37]/[C:36]1[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=1
Reactant: Fc1cc2c(cc1Br)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccc(/C=C/c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(F)c(Br)cc23)cc1
Yield: 74.1 %

Procedure:
A solution of 3.0 g of 5-bromo-6-fluoro-3-iodo-1-trityl-1H-indazole, 628 mg of 4-fluorostyrene, 115 mg of palladium acetate, 307 mg of 2-(di-ter-butylphosphino)biphenyl and 3.60 mL of triethylamine in N,N-dimethylformamide was stirred at 70° C. for a day. After diluting with ethyl acetate, washing successively with aqueous ammonium chloride and saturated brine, and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:100), to afford 2.2 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][C:3]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.C([Li])CCC.CCCCCC.[CH2:32]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH3:33].[Cl-].[NH4+]>C1COCC1>[CH2:32]([O:34][CH2:35][C:36]([C:2]1[S:6][C:5]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][C:3]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[O:37])[CH3:33]
Reactant: CCOCC(=O)N(C)OC
Reactant: CN(C(=O)OC(C)(C)C)c1nc(-c2ccco2)c(Br)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCC(=O)c1sc(N(C)C(=O)OC(C)(C)C)nc1-c1ccco1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
tert-Butyl N-[5-bromo-4-(2-furyl)thiazol-2-yl]-N-methylcarbamate (1.41 g, 3.93 mmol) obtained in Step 1 was dissolved in THF (19 mL), and a 1.57 mol/L solution of n-butyllithium in n-hexane (2.75 mL, 4.32 mmol) was added thereto in a stream of argon at −78° C., followed by stirring at −78° C. for 15 minutes. 2-Ethoxy-N-methoxy-N-methylacetamide (1.74 g, 11.8 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 623 (550 mg, 38%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH:9](Br)[O:10][CH2:11][CH3:12].O.Cl>CCOCC>[Br:7][CH2:8][CH:9]([O:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCOC(Br)CBr
Reactant: CCCC[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCCC(CBr)OCC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.68 moles of n-butylmagnesium bromide, as a 1.7 M solution in ether, is added dropwise a solution of 300 g. of 1,2-dibromo-2-ethoxyethane in 750 ml. of ether during a period of 2 hours at -15° C. The resultingmixture is stirred for one hour while warming to 20° C., then cooled to 0° C., and treated while stirring with 500 ml. of water, followed by 100 ml. of 4 N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The residue is distilled to provide a colorless liquid, b.p. 83°-84° C., 18 mm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]#[N:12].[NH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>C(#N)C>[C:11]([CH2:10][CH2:9][CH2:8][NH:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)#[N:12]
Reactant: N#CCCCCl
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCNC1CCc2ccccc21

Procedure:
Potassium carbonate (15.5 g, 112 mmole) and 4-chlorobutyronitrile (11.58 g, 112 mmole) was added to a solution of 1-aminoindan (5.0 g, 37.6 mmole) in acetonitrile (50 ml), and the mixture refluxed for 2 hr. A second portion of 4-chlorobutyronitrile (5.0 g) was then added, the mixture further heated for 24 hr, filtered and the filtrate evaporated to dryness. Unreacted 4-chlorobutyronitrile was removed by treating the residue (20 g) with isopropanolic HCl (16.7 ml, 24%) followed by successive extractions with ether (3×150 ml). The crude product thus obtained was further purified by column chromatography (Silica, CH2Cl2 :MeOH 98:2) to afford 3.7 g (49%) of tan-colored crystalline mass.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:24])=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.[CH3:26][O:27][NH2:28].C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]([Cl:24])=[C:5]([C:7](=[N:28][O:27][CH3:26])[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=CCS[C@H]23)c(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl

Procedure:
In a similar procedure to that of Example 2-1, 7β-[2-(2-amino-5-chloro-4-thiazolyl)glyoxylylamino]-3-cephem-4-carboxylic acid (276 mg) is treated with methoxyamine hydrochloride (58 mg) in methanol (5 ml) in the presence of sodium carbonate (74 mg) to afford 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid. Similarly prepared are compounds of Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:17])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: N
Product: NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 100 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and ammonia (10 mL, ca. 7N in methanol) were stirred together for 16 hours. 4-bromo-2-(trifluoromethoxy)benzenesulfonamide (0.33 g, 100%) was provided after purification. MS (ESI) m/z 320. HPLC purity 100.0% at 210-370 nm, 8.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:30]=[CH:29][C:17]3[CH2:18][CH:19]([CH2:24][C:25]([O:27]C)=[O:26])[C:20](=[O:23])[NH:21][CH2:22][C:16]=3[CH:15]=2)[CH:4]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:30]=[CH:29][C:17]3[CH2:18][CH:19]([CH2:24][C:25]([OH:27])=[O:26])[C:20](=[O:23])[NH:21][CH2:22][C:16]=3[CH:15]=2)[CH:4]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3cc(OC)ccn3)cc2CNC1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Solvent: O
Product: COc1ccnc(NCCCOc2ccc3c(c2)CNC(=O)C(CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 1(c), except substituting methyl (±)-8-[3-[(4-methoxy-2-pyridyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as an off-white solid: MS (ES) m/e 400.3 (M+H)+. Anal. Calcd for C21H25N3O5.0.75 H2O: C, 61.08; H, 6.47; N, 10.18. Found: C, 61.15; H, 6.20; N, 10.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:7][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(Cc2cc(Br)ccc2OC)cc1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 3 using 5-bromo-2-methoxybenzaldehyde and 4-bromophenetole.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[O:5][C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][CH:9]=[C:8]([O:14]CC=C)[C:7]=2[CH3:18])#[N:2].CO.C(N(CC)[C:25]1[CH:30]=CC=C[CH:26]=1)C>>[C:1]([C:3]1[C:4](=[O:19])[O:5][C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][C:9]([CH2:30][CH:25]=[CH2:26])=[C:8]([OH:14])[C:7]=2[CH3:18])#[N:2]
Reactant: C=CCOc1ccc2c(C)c(C#N)c(=O)oc2c1C
Reactant: CCN(CC)c1ccccc1
Solvent: CO
Product: C=CCc1cc2c(C)c(C#N)c(=O)oc2c(C)c1O
Yield: 76 %

Procedure:
A solution of 3-cyano-4,8-dimethyl-7-allyloxycoumarin (1.27 g, 4.97 mmoles) in 14 mL of N,N-diethylaniline was deoxygenated with argon for 30 minutes, and then was heated at reflux for 6 hours, while being purged by bubbling argon through the solution. The reaction mixture was chilled in ice, the resulting precipitate was collected by suction filtration and dried in vacuo. Recrystallisation from a mixture of benzene:methanol gave 0.97 g (76% yield) of 3-cyano-4,8-dimethyl-6-allyl-7-hydroxycoumarin (3, R═CN, R′=H) as a pale brown solid: mp 234-235° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[C:23]([O:26][CH2:27][CH2:28][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)OCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO2 ; eluted with MeOH 2%-4% in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The salt crystallized out at room temperature to yield 3.44 g (57%), m.p.=154°-155° C.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].P.[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:6]([O:14][P:1]([Cl:4])[Cl:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: ClP(Cl)Cl
Reactant: CCCCCCCCO
Agent: P
Product: CCCCCCCCOP(Cl)Cl
Temperature: 0 °C

Procedure:
Freshly distilled phosphorus trichloride (45.6 g, 0.338 mole) was charged into a four-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a thermometer, and a reflux condenser itself topped with a discharge tube. The discharge tube led to an aqueous sodium hydroxide trap for absorption of hydrogen chloride that evolves from the reaction. After cooling the reaction vessel to 0° C. with continual purging of dry nitrogen, anhydrous octanol (22 g, 0.168 mole) was added dropwise to the reaction mixture. When the addition of the octanol was complete, the reaction mixture was allowed to warm gradually up to room temperature and was then poured into a dry distillation flask. The material was distilled with a bath temperature of 80–85° C. and using a water pump vacuum to remove residual hydrogen chloride and excess phosphorus trichloride. The residue was then fractionated at 8 mm Hg to yield the product at 113–130° C. in 69% conversion. The phosphorus-31 NMR showed a peak at 176 ppm. The refractive index at 21.5° C. was 1.4682.
Reaction SMILES: C1([O:7][C:8]([N:10]2[C:16]([CH3:17])=[CH:15][C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=3)=[N:11]2)=O)C=CC=CC=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:8]([N:10]2[C:16]([CH3:17])=[CH:15][C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=3)=[N:11]2)=[O:7])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)NC1CC1
Yield: 59 %

Procedure:
2.07 g (4.6 mmoles) 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine-3-carboxylic acid phenyl ester are boiled in 10 ml of cyclopropylamine for 10 hours. The separated crystals are filtered off, and the crude product is re-crystallized from ethanol. Thus 1.12 g (59%) of the desired compound melting at 221-223° C. is obtained.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:15][CH3:16].[F:17][C:18]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1CCCCC1.CCOC(C)=O>[CH3:16][O:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([O:13][CH3:14])=[C:11]([CH3:12])[C:2]=1[C:20]([C:19]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:18]=1[F:17])=[O:21]
Reactant: COc1c(C)c(Br)c(OC)c2ccccc12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1c(C)c(C(=O)c2ccc(C(F)(F)F)cc2F)c(OC)c2ccccc12

Procedure:
2-bromo-1.4-dimethoxy-3-methylnaphthalene (300 mg, 1.07 mmol) and commercially available 2-fluoro-4-trifluoromethyl-benzoylchloride (265 mg. 1.17 mmol) were treated according to general procedure 12.1. The resulting yellow oil was purified through flash chromatography (Cyclohexane:EtOAc 10:1). The product was obtained as a yellow oil. Rf(Cyclohexane:EtOAc 10:1)=0.50. Yield=175 mg (42%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)[CH2:11][CH2:10]2)=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.CN([CH:31]=[O:32])C.[NH4+].[Cl-]>C1COCC1.O>[CH3:7][C:5]1[N:6]=[C:2]([CH:31]=[O:32])[S:3][C:4]=1[CH2:8][N:9]1[CH2:14][CH2:13][C:12]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:11][CH2:10]1
Reactant: CN(C)C=O
Reactant: Cc1nc(Br)sc1CN1CCC2(C=Cc3ccccc32)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C=O)sc1CN1CCC2(C=Cc3ccccc32)CC1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 2-bromo-4-methyl-5-(spiro[indene-1,4′-piperidine]-1′-ylmethyl) thiazole (3.8 g, 10.12 mmol) in THF is added n-BuLi (0.713 g, 11.13 mmol) at −78° C. The mixture is warmed to −45° C. and stirred for 30 minutes. DMF (1.5 mL) is added dropwise to the mixture at −78° C. and the mixture is slowly warmed to room temperature and stirred for an hour. The mixture is cooled to −78° C., diluted with water, followed by NH4Cl solution. The mixture is extracted with ethyl acetate, dried over Na2SO4, and evaporated to dryness to give the title compound (2.8 g, 85%). ESI/MS m/z 325 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([N:6]2[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]2)[N:18]=1
Reactant: FC1(F)CCNCC1
Reactant: Clc1cncc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC1(F)CCN(c2cncc(Cl)n2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of 4,4-difluoropiperidine hydrochloride (598 mg, 3.79 mmol), Cs2CO3 (2471 mg, 7.58 mmol) and 2,6-dichloropyrazine (538 mg, 3.61 mmol) in DMF (5 mL) was heated in a microwave at 100° C. for 35 min. The mixture was diluted with EtOAc (50 mL) and washed with 2×5 mL of H2O. The organic layer was dried, filtered and concentrated. The residue was purified on a silica gel column (eluting with 25-35% EtOAc in Hex) to give 2-chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine (717 mg, 85%) as a brown amorphous solid. MS (ESI, pos. ion) m/z 234.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.89 (s, 1H), 3.75 (t, J=5.7 Hz, 4H), 2.06 (m, 4H).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[N:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:12]=1[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:15]3[CH:16]=[N:11][C:12]([CH3:26])=[CH:13][CH:14]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2nn3c(I)cnc3s2)cn1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (169 mg, 0.512 mmol, 1 eq), 2-picoline-5-boronic acid pinacol ester (137 mg, 0.614 mmol, 1.2 eq), PdCl2(PPh3)2 (73 mg, 0.102 mmol, 0.2 eq) and 2M aq Na2CO3 (1.5 mL) in dioxane (7 mL) was heated at 110° C. for 2 h. The solvent was removed under reduced pressure, redissolved in dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated. The residue (226. mg) was used in the next step of the synthesis without further purification. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mUrnin, 50° C.): tR=3.79 min, [M+H]+ m/z 342.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1I.[CH3:16][C:17]1[CH:18]=[N:19][NH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I.O.ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:19]1[CH:18]=[C:17]([CH3:16])[CH:21]=[N:20]1
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1I
Reactant: Cc1cn[nH]c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1-n1cc(C)cn1
Temperature: 120 °C
Yield: 57 %

Procedure:
In a glass tube was added successively 0.29 mmol 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester (example B19(c)), 0.35 mmol 4-methylpyrazole, 0.59 mmol potassium carbonate, 0.06 mmol CuI and a solution of 0.12 mmol trans-1,2-diaminocyclohexane in 0.4 ml dioxane (degassed). The tube was filled with argon and sealed with a cap. The reaction mixture was heated at 120° C. overnight. The reaction mixture was cooled down to room temperature, dichloromethane and water were added. The aqueous phase was extracted 2 times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude compound was purified on a log Flashpack cartridge. Eluent: Heptane/ethylacetate to provide the title compound (57%) as a light yellow oil. MS (m/e): 295.0([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:51][OH:52])[CH2:53][OH:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 21m (0.52 g, 0.68 mmol) in methanol (20 mL) was added sodium borohydride (52 mg, 1.37 mmol) at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL×4). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21n as light yellow oil (0.52 g, 100%). This material was not further purified
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3Br)[NH:10]/[C:11]/2=[N:12]\[O:13][C@@H:14]([CH2:20][CH2:21][OH:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]=1.[CH3:32][O:33][C:34]1[N:39]=[C:38](B2OCCN(C3C=CC=CC=3)CCO2)[CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH3:32])[N:39]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][C@@H:14]([CH2:20][CH2:21][OH:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]=1
Reactant: Cc1nc(N)nc2c1/C(=N/O[C@@H](CCO)C(=O)N(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O[C@@H](CCO)C(=O)N(C)C)N2)n1
Temperature: 85 °C
Yield: 37.8 %

Procedure:
A mixture of (S)-2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (26 mg, 0.052 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (78 mg, 0.262 mmol), Pd(dppf)2Cl2 (7.68 mg, 0.01 mmol), 2N aq Na2CO3 (0.131 mL, 0.262 mmol) and DMA (2.0 mL) was degassed with N2 and heated at 85° C. for 4 h. Cooled to r.t., filtered trough celite and purified by prep LCMS to afford (S)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (93, 10.3 mg, 37%) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.04-2.15 (m, 2H) 2.60 (s, 3H) 2.97 (s, 3H) 3.01-3.07 (m, 1H) 3.13 (s, 3H) 3.30 (ddd, J=16.42, 3.79, 1.52 Hz, 1H) 3.70-3.84 (m, 2H) 3.89 (s, 3H) 4.90 (dd, J=10.74, 3.66 Hz, 1H) 5.12 (t, J=6.32 Hz, 1H) 5.26 (br. s., 1H) 5.78 (s, 1H) 6.74 (dd, J=8.34, 0.76 Hz, 1H) 7.02 (dd, J=7.20, 0.88 Hz, 1H) 7.11-7.21 (m, 2H) 7.65 (dd, J=8.34, 7.07 Hz, 2H). MS (ES) [M+H] calculated for C26H31FN7O4, 524.56. found 524.40.