Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH:27]([NH:30][C:31]([CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1)=[O:32])([CH3:29])[CH3:28]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH:33]2[C:31](=[O:32])[NH:30][CH:27]([CH3:28])[CH3:29])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: CC(C)NC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NC(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 29.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.57 g, 1.2 mmol) was reacted with N-isopropylmorpholine-3-carboxamide (0.21 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.2 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.Cl>O1CCOCC1>[NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.9 %

Procedure:
4-(1,1-Dimethylethyl) 2-(phenylmethyl) 2,4-morpholinedicarboxylate (1.19 g, 3.70 mmol) was dissolved in 1,4-dioxane (2 ml). Hydrogen chloride (4M) in 1,4-dioxane (20 ml, 80 mmol) was added and the mixture was stirred at room temperature under nitrogen for 4 hr. The solvent was removed in vacuo to give a white solid. The solid was dried in a vacuum oven overnight to give the title compound (908 mg) as a white solid.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=[CH:4]2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-n2cnc(I)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.18) (0.33 g, 0.77 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.203 g, 0.92 mmol) according to the general procedure VI. Obtained as an off-white solid (0.100 g, 33%). MS (ISP) 396.1 [(M+H)+]; mp 224-226° C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:11]([Li])CCC.CI>C1COCC1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([CH2:4][O:5][CH3:11])[C:2]=1[NH2:1]
Reactant: [Li]CCCC
Reactant: Nc1c(Cl)cccc1CO
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1cccc(Cl)c1N
Yield: 25.2 %

Procedure:
A solution of 4.00 g (25.4 mmol) of 2-amino-3-chlorobenzyl alcohol in 30 ml of dry THF was cooled to -78° C., treated with 16.7 ml (26.7 mmol) of 1.60M n-butyllithium in hexane, warmed to 0°-5° C., treated with 3.61 g (25.4 mmol) of methyl iodide and heated at reflux for 5.5 hours. The solvent was removed by evaporation at reduced pressure. The residue was partitioned between 175 ml of ether and water, and the organic phase was separated and dried (MgSO4). The solvent was removed by evaporation at reduced pressure, and the residue was purified by HPLC eluting with EtOAc and hexane (5:95, v/v) to afford 1.1 g of the desired product as a pale brown oil. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:12][C:11]([F:13])([F:14])[CH2:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccccc1OCC(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccccc1OCC(F)(F)F
Yield: 66.4 %

Procedure:
To a solution of 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (3.83 g) in dry methylene chloride (50 ml) was added boron tribromide (3.1 ml) with stirring under ice cooling, and the mixture was reacted for 30 minutes. The reaction mixture was poured into an aqueous sodium bicarbonate solution (500 ml), and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and diethyl ether (20/1) as eluent to give 2.37 g of 2-(2,2,2-trifluoroethoxy)phenol melting at 49°-50° C.
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:26][O:27][CH3:28])[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.Cl>C(OCC)C>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:26][O:27][CH3:28])[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cccc(N)n1
Yield: 52.3 %

Procedure:
A solution of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (2.3 g.) in methanolic hydrochloric acid (12 ml., containing hydrochloric acid 6 mmol) was stirred at room temperature for one hour. To the resultant solution was added diethyl ether, and the precipitates were collected by filtration and dissolved in a mixture of methanol (50 ml.) and water (10 ml.). The solution was adjusted to pH 3 with an aqueous solution of sodium bicarbonate, treated with activated charcoal (1 g.) and concentrated to a volume of about 20 ml. The precipitating crystals were collected by filtration, washed with water and dried to give 7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (1.12 g.), mp. 215° to 220° C. (dec.). The mother liquor and washings were combined and concentrated under reduced pressure. The appeared precipitates were collected by filtration, washed with water and dried to give the same object compound (0.36 g.). Total yield 1.48 g.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)#[N:17].N1CCCCC1.O>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][C:16]#[N:17])[CH:21]=1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Reactant: N#CCOc1cccc(C=O)c1
Solvent: O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: N#CCOc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
In 5 ml of chloroform were dissolved 0.57 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 0.45 g of 3-(cyanomethoxy)benzaldehyde and 0.20 g of piperidine, and the solution was heated under refluxing for 1 hour and 30 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction mixture washed successively with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. Precipitated crystals were washed with a mixture of 10 ml of dioxane and 10 ml of chloroform, and washed with 10 ml of t-butyl methyl ether to obtain 0.56 g of 4-hydroxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (14d)] as a yellow crystal.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2cnc3ccc(NC4CCC(O)CC4)nn23)c1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
To a solution of 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile (300 mg, 1.18 mmol) and trans-4-aminocyclohexanol hydrogenchloride (678 mg, 5.89 mmol) in NMP (2.0 mL) was added NaHCO3 (496 mg, 5.89 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-cyano phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (110 mg, 28%) as a pale yellow solid.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]2[N:15]([CH2:19][CH2:20][CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:14]=[N:13][C:12]=2[N:11]([CH3:31])[C:9]1=[O:10])C1C=CC=CC=1.N>C(O)C.[Pd]>[CH3:31][N:11]1[C:12]2[N:13]=[CH:14][N:15]([CH2:19][CH2:20][CH2:21][CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:16]=2[C:17](=[O:18])[NH:8][C:9]1=[O:10]
Reactant: CCOP(=O)(CCCCn1cnc2c1c(=O)n(Cc1ccccc1)c(=O)n2C)OCC
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)[nH]c(=O)n2C)OCC
Reaction time: 48 h

Procedure:
13 g (0.03 mol) of diethyl [4-(1-benzyl-3-methylxanthin-7-yl)-butyl]phosphonate were suspended in 150 ml of ethanol with 2 g of palladium on activated carbon (10%) and, after addition of 3 ml of concentrated ammonia solution, hydrogenated with shaking at 1.5 bar in the course of 48 hours. The catalyst was filtered off, the solvent was evaporated under reduced pressure and the residue which remained was crystallized from diisopropyl ether.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH:6]([C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.CCOCC.O>ClCCl>[CH:2]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=2)[CH2:5][CH2:4]1)=[O:1]
Reactant: CCOC(=O)c1ccc(C2CCC3(CC2)CO3)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reaction time: 2 h

Procedure:
1.4 g of ethyl 4-(1-oxaspiro[2.5]oct-6-yl)benzoate (5.38 mmol, 1.4 eq.) are placed in 40 mL of dichloromethane at 4° C. 0.229 g of boron trifluoride etherate (1.61 mmol, 0.3 eq.) is added with stirring. After 2 hours, 0.153 g of boron trifluoride etherate (1.07 mmol, 0.2 eq.) is added. After 1 hour, water is added and the reaction medium is extracted three times with dichloromethane. The organic phases are combined and washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with an 88/10/2 mixture of heptane/ethyl acetate/methanol. 0.64 g of ethyl trans-4-(4-formylcyclohexyl)benzoate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: C#CCOc1cc(C=Nc2ccccc2)cc(Cl)c1OCC#C
Yield: 101.1 %

Procedure:
A mixture of 3-chloro-4,5-dipropargyloxybenzaldehyde (1.00 g) and aniline (0.37 g) in benzene (30 ml) was stirred under reflux for 3 hours, followed by concentration under reduced pressure to give N-(3-chloro-4,5-dipropargyloxybenzyliden)aniline (1.30 g). nD23.0 1.5890.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[CH:5]=[CH:4][N:3]=1.[Cl:10]Cl>>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Nc1nccc(Br)c1O
Reactant: ClCl
Product: Nc1ncc(Cl)c(Br)c1O

Procedure:
The procedure of Example I-12 is followed with 2-amino-4 -bromo-3-pyridinol and chlorine to give 2-amino- 4-bromo-5-chloro-3-pyridinol.
Reaction SMILES: [CH:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]O)=[CH:22][CH:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>CCOCC>[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][C:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1ccc([N+](=O)[O-])cc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
To a solution of triethyl methanetricarboxylate (16.6 g) in ether (350 mL) were added 4-nitrophenethyl alcohol (8.00 g) and triphenylphosphine (25.0 g). 40% Diisopropyl azodicarboxylate/toluene solution (48.4 g) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Insoluble material was removed by filtration, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (12.2 g) as an oil.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([CH2:18]O)[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(Cl)Cl.[N-:24]=[N+:25]=[N-:26].[Na+]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([OH:20])[CH:16]([CH2:18][N:24]=[N+:25]=[N-:26])[CH2:17]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(CO)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(O)C(CN=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Ms-Cl (0.38 mL, 2.6 eq) was added to a solution of 3-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of stereoisomers, prepared according to WO9303026, 410 mg, 1.89 mmol) in pyridine (3.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then DCM was added and the mixture was washed with sat. aq. NaHCO3, dried over MgSO4, concentrated under reduced pressure and dried at HV. The crude mesylate was dissolved in DMF (18 mL), treated with NaN3 (1.23 g, 10 eq) and stirred at 95° C. for 1.5 h. After cooling to rt the mixture was concentrated to dryness and dissolved in DCM. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and the residue was purified by CC (DCM to DCM/MeOH 95:5) to afford the title intermediate as a yellow oil (390 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:16][B:17](OC(C)C)[O:18]C(C)C)(C)C.C([Li])CCC.Cl>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([B:17]([OH:18])[OH:16])=[CH:4][N:3]=1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)ncc(B(O)O)c2s1
Temperature: -75 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
4-Chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B) (2.35 g, 7.56 mmol) and triisopropylborate (1.8 ml, 7.94 mmol) were dissolved in 70 ml THF and cooled to −75° C. n-Butyllithium (1.6M in hexane) (5.0 ml, 7.94 mmol) was added drop wise at −70° C. The reaction mixture was stirred for 1 hour at −75° C. and for 1 hour without ice-bath. 10 ml 2N HCl-solution were added and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized in acetonitrile to get the desired compound as a red solid (520 mg, 30%), MS: m/e=229.2 (M+H+).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13]([C@H:15]1[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:18]=[C:17]([C:33]([O:35][CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[O:16]1)=O.[CH3:49][NH:50][CH2:51][CH2:52][CH3:53]>>[CH:36]([O:35][C:33]([C:17]1[O:16][C@@H:15]([C:13](=[O:12])[N:50]([CH3:49])[CH2:51][CH2:52][CH3:53])[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH:18]=1)=[O:34])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCCNC
Reactant: CC(=O)N[C@@H]1[C@@H](NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Product: CCCN(C)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To (2R,3R,4S)-3-acetylamino-4-(tert-butoxycarbonylamino)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid 6-benzhydryl ester 2-(2,3,4,5,6-pentafluoro-phenyl) ester (1.18 g) in dry tetrahydroduran (13 ml) was added N-methyl-propylamine (0.152 g) and the reaction was stirred at 23° C. for 4 hours. The solvent was removed in vacuo and the residue was chromatographed over silica (Merck 9385, 150 g) using medium pressure (~4 psi) and ethyl acetate as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam. (0.85 g); 1H NMR (250 MHz, D6 -DMSO) 8.10-7.98 (1H, m), 7.48-7.26 (10H, m), 6.91 (1H, s), 6.58 (1H, m), 6.03 (1H, m), 5.13 (1H, m), 4.34 (1H, m), 4.03 (1H, m), 3.37 (2H, m), 3.07+2.81 (3H, s), 1.77 (3H, s), 1.64-1.22 (2H, m), 1.37 (9H, s), 0.81 (3H, m): Mass spec (Low resolution): MH+ =566, MH+ -BOC=466; Mass analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].C(OC(=O)[NH:21][OH:22])(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(#N)C.CCOC(C)=O.O>[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][O:22][NH2:21]
Reactant: CC(C)(C)OC(=O)NO
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1cc(CON)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzyl chloride (1.00 g, 4.6 mmol) and tert-butyl-N-hydroxycarbamate (0.62 g, 4.6 mmol) in acetonitrile (20 ml) was added Cs2CO3 (4.51 g, 13.8 mmol). The reaction mixture was stirred at room temperature for 24 hours. Water was added and the products extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by chromatography on silica using a gradient of EtOAc in petroleum ether (0-40%, v/v) affording 411 mg of Boc-protected O-(3,4,5-trimethoxy-benzyl)-hydroxylamine. This intermediate (383 mg/1.22 mmol) was treated with 37% hydrochloric acid (2.5 ml) in EtOAc (7.5 ml) for 30 min. at room temperature. The mixture was concentrated under reduced pressure and diethyl ether was added. The resulting precipitated material was isolated by filtration and dried under high vacuum affording the title compound (211 mg) as white shiny crystals.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[CH:53]=[CH:52][N:51]=[CH:50][C:49]=1[N+:54]([O-:56])=[O:55].[NH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:54]([C:49]1[CH:50]=[N:51][CH:52]=[CH:53][C:48]=1[NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1)([O-:56])=[O:55]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Pd(OAc)2 (9.5 mg, 0.042 mmol) and BINAP (26 mg, 0.042 mmol) were combined in toluene (1 ml) and stirred at rt for 10 minutes. This mixture was then added to a sealed vessel which contained 4-chloro-3-nitropyridine (172 mg 1.0 mmol), 2-aminopyridine (100 mg, 1.0 mmol), and K2CO3 (160 mg, 1.2 mmol) in toluene (2 ml). The reaction was heated to 110° C. for 2 h. The reaction was filtered while hot and the filter cake washed with EtOAc. The combined filtrates were concentrated and purified on 16 g SiO2 with 0-40% EtOAc hexanes. MS (ESI): mass calcd. for C10H8N4O2, 216.0. m/z found, 217.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.35 (s, 1H), 8.81 (d, J=6.2 Hz, 1H), 8.50 (d, J=6.1 Hz, 1H), 8.44 (dd, J=5.0, 1.2 Hz, 1H), 7.74 (ddd, J=8.2, 7.4, 1.9 Hz, 1H), 7.09 (ddd, J=7.4, 5.0, 0.9 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[C:12]([C:20]([OH:22])=[O:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>C1COCC1>[OH:19][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[C:20]([OH:22])=[O:21]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Cc1ccccc1Br
Agent: II
Agent: [H-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of magnesium (0.773 g, 31.81 mmol), iodine (cat. Amount) in THF (20 ml) is added dropwise, bromotoluene (3.83 ml, 31.81 mmol) in THF (30 ml). The reaction mixture is warmed to initiate the reaction and then allowed to stir at room temperature for 30 minutes. Meanwhile, a second mixture comprising benzoyl formic acid (4.342 g, 28.92 mmol) in THF (50 ml) is cooled in an ice bath. Sodium hydride (1.156 g of a 60% dispersion in mineral oil, 28.92 mmol) is added to the mixture, portionwise, ensuring the temperature does not rise above 10° C. Then the grignard reagent which has been stirring for 30 minutes is added dropwise and the reaction mixture is allowed to warm to room temperature. After stirring for 21 hours, the reaction mixture is partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer is acidified to pH 1 with 1 M hydrochloric acid and then extracted with ethyl acetate. The organic portions are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The crude residue is purified by chromatography on silica (eluting with ethyl acetate) to yield the titled compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][C:35]3[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=3[CH:29]=2)O1>>[CH3:38][C:34]1([CH3:39])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]2[CH:29]=[C:28]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[CH:37]=[CH:36][C:35]1=2
Reactant: OCCCNC1CCCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS102 starting from 107 mg (0.323 mmol) of 3-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]propan-1-ol and 123 mg (0.356 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The crude product is purified by means of RP flash chromatography on C18 silica gel. The product is in the form of the hydrochloride.