Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.7 %

Procedure:
To a N,N-dimethylformamide (DMF) (15 ml) solution of (4-tert-butylphenoxy)acetic acid (312 mg, 1.50 mmol) and N-[4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (451 mg, 1.80 mmol), 1-ethyl-3-(3′-dimethylaminopr6pyl)carbodiimide hydrochloride (EDC) (518 mg, 2.70 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol) and triethylamine (607mg, 6.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=100/1 to furnish 350 mg (58% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:4][C:3]=1[NH:18][C:19](=O)[O:20]C(C)=C.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][NH2:29].CN1CCCC1>O1CCOCC1>[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][NH:29][C:19]([NH:18][C:3]1[CH:4]=[C:5]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13]2)[C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[O:20]
Reactant: CC(C)(C)CCN
Reactant: C=C(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 75 °C
Yield: 87.9 %

Procedure:
Treat a solution of prop-1-en-2-yl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (6.67 g, 19.90 mmol) in dioxane (60 mL) with 3,3-dimethylbutan-1-amine (2.42 g, 23.9 mmol) and 1-methylpyrrolidine (0.169 g, 1.99 mmol) and heat at 75° C. overnight. Cool the mixture to RT, collect the solid via filtration and wash with diethyl ether to obtain the title compound (6.62 g, 88% yield over two steps). MS (m/z): 379.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:14])[CH2:12][Cl:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:15]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].Cl>C(OCC)C>[C:15]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:1]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:14])[CH2:12][Cl:13])=[CH:6][CH:5]=2)([OH:3])[CH3:2])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CC(=O)c1ccc(CC(C)CCl)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(CCl)Cc1ccc(C(C)(O)Cc2ccc(C(C)(C)C)cc2)cc1
Yield: 57 %

Procedure:
168.4 g of 3-(4-acetylphenyl)-2-methylpropyl chloride in 100 ml of diethyl ether were added dropwise to a Grignard suspension prepared from 182.5 g of 4-tert.-butylbenzyl chloride and 26 g of Mg in 400 ml of diethyl ether. After completion of the dropwise addition, the mixture was refluxed for a further 2 hours and then hydrolyzed by adding ice-cooled dilute aqueous HCl until the pH was 2. The organic products were extracted with ether, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 163.4 g of (VI) of boiling point 190° C./0.1 mbar.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ6 10.31 (bs, 1H), 10.04 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.75 (t, 1H, J=3.0 Hz), 7.54 (td, 1H, J=3.0 and 9.0 Hz), 7.34 (s, 1H), 7.20-7.15 (m, 2H), 6.80 (d, 1H, J=8.1 Hz), 5.38-5.31 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.49 (dd, 1H, J=11.1 and 16.5 Hz); LCMS: purity: 99%; MS (m/e): 446 (MH+).
Reaction SMILES: CC(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][N:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1)C)(C)C.Cl>>[CH3:6][NH:7][CH2:9][CH2:10][CH2:11][N:12]([C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35]
Reactant: CN(CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
[3-[(2-Benzoylphenyl)(3-nitro-2-pyridinyl)amino]propyl]methyl carbamic acid 1,1-dimethylethyl ester is hydrolyzed in an aqueous solution of hydrochloric acid to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][CH:21]=O)[CH:15]=[CH:16][C:17]=1[F:18]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][CH:21]2[NH:10][CH2:9][CH2:8][N:3]3[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]23)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=CCCc1ccc(F)c(F)c1
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1nc(C)n2c1C(CCc1ccc(F)c(F)c1)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(3,4-difluoro-phenyl)-propionaldehyde. LC-MS: tR=0.57 min.; [M+H]+=292 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13](Cl)=[C:4]2[CH:3]=1.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][SH:23].[OH-].[K+]>C(O)C>[NH2:19][CH2:20][CH2:21][CH2:22][S:23][C:13]1[C:12]2[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=12
Reactant: CN1CCc2nc3ccc(Cl)cc3c(Cl)c2C1
Reactant: NCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2nc3ccc(Cl)cc3c(SCCCN)c2C1
Yield: 52.9 %

Procedure:
A solution of 5.0 g (0.0188 mol) of the compound of Example 6, 3.3 g (0.02244 m) of 3-aminopropanethiol hydrochloride, 15 ml of 18.5% aqueous potassium hydroxide (0.05 m) and 30 ml of absolute ethanol is refluxed for one and a half hours. After evaporation of the solution, the residue is dissolved in methylene chloride and extracted with water. Evaporation of the methylene chloride solution gives the free base. Recrystallization of the product from hexane affords the title compound as a crystaline solid (3.2 g, 53%), m.p. 87°-89° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].Cl.N>O>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=2)[CH:7]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: N
Solvent: O
Product: Cc1cc(NCc2cccc(C(F)(F)F)c2)nc(-c2ccccn2)n1
Yield: 24.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol), 3-trifluoromethylbenzylamine (70.1 mg, 0.4 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed for two days. The resulting solution was basified to pH ˜11 with ammonia and extracted with ethyl acetate (10 ml×3). The combined ethyl acetate extracts were dried with sodium sulfate, and evaporated under vacuum. The residue was purified by column chromatography (hexane/ethyl acetate: 1/1) to give the title compound as a solid (34 mg, 25%). 1H NMR (CD3OD): 8.59 (d, J=4.2 Hz, 1H), 8.27 (m, 2H), 7.86 (m, 2H), 7.43 (m, 2H), 6.18 (s, 2H), 4.76 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][NH:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][N:30]([C:18]2[C:19]([F:21])=[CH:20][C:10]3[C:11]([CH:17]=2)=[N:12][C:13]2[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=2[CH:9]=3)[CH2:29]1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN(C)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Temperature: 95 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, 1.2 g of 3-(dimethylamino)azetidine dihydrochloride and 1.5 g of sodium carbonate in 30 cm3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95° C. for 5 hours. After cooling to approximately 20° C., the reaction mixture is treated with 60 cm3 of water. The insoluble matter is drained and washed with 3 times 20 cm3 of water. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine are obtained in the form of a yellow solid, melting point 224° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [C:1](Cl)(C(Cl)=O)=O.[O:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:9]=[C:8]1[C:16]([OH:18])=[O:17]>C(Cl)Cl>[CH3:1][O:17][C:16]([C:8]1[O:7][C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:9]=1)=[O:18]
Reactant: O=C(O)c1cc2cnccc2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc2cnccc2o1
Reaction time: 1 h

Procedure:
(COCl)2 (2.5 mL) was added dropwise to a stirred suspension of furo[3,2-c]pyridine-2-carboxylic acid (1.64 g, 10.1 mmol) in anhydrous CH2Cl2 (40 mL). After effervescence had ceased, the mixture was concentrated. Further CH2Cl2 (20 mL) was added, followed by NEt3 (4 mL) and MeOH (20 mL). After 1 h stirring, the mixture was diluted with EtOAc (50 mL) and washed with H2O, saturated aqueous NaHCO3 and brine. The CH2Cl2 solution was dried (MgSO4), filtered, and concentrated to afford furo[3,2-c]pyridine-2-carboxylic acid methyl ester: δH(CDCl3): 3.96 (s, 3H), 7.48 (d, 1H), 7.54 (s, 1H), 8.59 (d, 1H), 9.00 (s, 1H). A solution of this compound (1.10 g, 6.2 mmol) in MeOH was treated with TFA (0.5 mL). The flask was purged with argon, Bz2O2 (1.50 g, 6.2 mmol) added, and the mixture heated to reflux for 8 h. The mixture was cooled, adsorbed onto silica and purified via column chromatography to furnish 4-hydroxymethylfuro[3,2-c]pyridine-2-carboxylic acid methyl ester: m/z (ES+)=208.0 [M+H]+. A solution of this alcohol (0.50 g, 2.4 mmol), tBDMS-Cl (0.47 g, 3.1 mmol), NEt3 (0.5 mL, 3.6 mmol) and DMAP (catalytic) was stirred in THF overnight. The solution was diluted with EtOAc and washed with H2O and brine, before being dried and concentrated. Purification via chromatography afforded 4-(tert-butylmethylsilanyloxymethyl)furo[3,2-c]pyridine-2-carboxylic acid methyl ester: δH (CDCl3) 0.01 (s, 6H), 0.82 (s, 9H), 3.86 (s, 3H), 4.99 (s, 2H), 7.28 (d, 1H), 7.87 (s, 1H), 8.38 (d, 1H). To a solution of 4-(N-hydroxycarbamimidoylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 9, 93 mg, 340 μmol) in THF was added NaH (60% dispersion in mineral oil, 14 mg, 350 μmol). After effervescence had ceased, 4-(tert-butylmethylsilanyloxymethyl)furo[3,2-c]pyridine-2-carboxylic acid methyl ester (100 mg, 311 μmol) was added. After 3 h at 20° C., the reaction was heated to reflux for 50 min. The mixture was cooled, diluted with EtOAc, washed with saturated aqueous NH4Cl, and brine, before being dried and concentrated. Purification via column chromatography afforded the title compound: m/z (ES+)=545.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12](Cl)[O:13][CH3:14].O>CN(C=O)C>[CH3:12][O:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-hydroxybenzaldehyde (1.22 g, 10 mmol) was dissolved in 100 ml dried DMF and stirred at room temperature. NaH (0.8 g) was added in to the reaction. After 10 min, MOMCl (1.5 ml) was added into the reaction by drop. Then the result solution was stirred at room temperature, and monitored by TLC. When the reaction was completed, 500 ml H2O was added. The resulting solution was extracted by ethyl acetate, and the organic layers were combined, dried by Na2SO4, concentrated by reduce pressure. The resulting oil was directly used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ: 3.50 (s, 3H), 5.26 (s, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 9.90 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([F:16])=[CH:6][C:7]2[O:12][CH:11]([CH3:13])[C:10](=[O:14])[NH:9][C:8]=2[CH:15]=1.[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O>[NH2:3][C:4]1[C:5]([F:16])=[CH:6][C:7]2[O:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH2:19][C:18]#[CH:17])[C:8]=2[CH:15]=1
Reactant: C#CCBr
Reactant: CC1Oc2cc(F)c(N)cc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)C(C)Oc2cc(F)c(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
While kept under N2, 0.30 g (7.4 mmol) of sodium hydride (60% dispersion in oil) was washed with 1 ml pentanes and then suspended in 2 ml anhydrous dimethylformamide. A solution of 1.36 g (6.9 mmol) of 6-amino-7-fluoro-2-methyl-2H-1,4-benzoxazin-3(4H)-one in 10 ml of dimethylformamide was added to the sodium hydride slurry slowly by syringe with ice cooling and the reaction mixture was stirred at room temperature for 0.5 hr. There was then added 0.77 ml (8.6 mmol) of propargyl bromide by syringe with ice bath cooling. The reaction mixture was allowed to warm to room temperature, stirred for 84 hours and then poured into 50 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml) and the organic layers were combined and washed with water (3×50 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo to yield a golden solid which was recrystallized from chloroform to yield 0.66 g of 6-amino-7-fluoro-2-methyl-4-propargyl-2H-1,4-benzoxazin-3(4H)-one as a brown solid, m.p. 142°-145° C.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[I:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH2:11][CH2:12][C:13](=[O:15])[CH3:14]
Reactant: II
Reactant: COc1cccc(CCC(C)=O)c1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(I)c(CCC(C)=O)c1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Samples of iodine (42.4 g, 0.167 mole) and silver acetate (27.87 g, 0.167 mole) were added in portions to a solution of 29.8 g (0.167 mole) of 1-(3-methoxyphenyl)- butane-3-one in 167 ml of glacial acetic acid. The mixture was stirred one hour. The silver iodide was removed by filtration and washed with acetic acid. The filtrate was partitioned between ether and water. The ether layer was washed with water, sodium bicarbonate solution and sodium thiosulfate solution. The ether solution was dried with MgSO4 and evaporated to dryness in vacuo. There was obtained 41.8 g (82% yield) of oily 1-(2-iodo-5-methoxyphenyl)butane-3-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][CH:14]([OH:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reaction time: 4.5 h

Procedure:
3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14 mmol) was dissolved in a 1:1 mixture of methanol (35.0 mL) and CH2Cl2 (35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0 mmol) was added slowly, gas evolution was observed. After 4.5 h at rt under nitrogen, the reaction was concentrated in vacuo. The crude mix was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using HPFC Jones 50 gram silica gel column eluting with 50% EtOAc: Hex to 100% EtOAc, to yield the title compound as a light yellow solid; MS (ES+): m/z 349.81 (100) [MH+], 351.50 (30) [MH+++]; HPLC: tR=2.49 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.41-2.54 (m, 2 H) 2.78-3.05 (m, 1 H) 3.12-3.32 (m, 1 H) 4.08-4.75 (m, 1 H) 5.30 (s, 1 H) 7.31 (d, J=5.05 Hz, 1 H) 7.57 (d, J=4.80 Hz, 1 H)
Reaction SMILES: [C@H:1]12[O:6][C@H:5]1[CH2:4][CH2:3][C@@H:2]2[N:7]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:8](=[O:14])[O:9]C(C)(C)C>CO>[OH:6][C@H:5]1[C@H:1]2[C@H:2]([N:7]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])[C:8](=[O:14])[O:9]2)[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N([C@H]1CC[C@@H]2O[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CO
Product: O=C1O[C@H]2[C@H](O)CC[C@H]2N1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (1R*,2S*,5S*)-6-oxabicyclo[3.1.0]hexan-2-yl((2-nitrophenyl)sulfonyl)-carbamate (2.0 g, 5.10 mmol) in MeOH (40 mL) was added Amberlyst 15 (4.0 g) and the resulting suspension was stirred for 1.5 h at 25° C. The reaction mixture was filtered and concentrated. The title compound was obtained after purification by flash chromatography (heptane-EtOAc 90:10→EtOAc) as a beige solid (1.24 g, 73%): TLC (heptane/EtOAc 1:2) Rf=0.36; tR=0.80 min (UPLC 1), tR, 0.77 min (LC-MS 3); ESI-MS: 346 [M+NH4]+ (LC-MS 3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1.O>C(#N)C>[N+:19]([C:16]1[S:15][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
To a solution of piperazine (18.2 g) and potassium carbonate (12.6 g) in acetonitrile (150 ml) was added 2-bromo-5-nitrothiazole (14.7 g) at 40° C. and the mixture was stirred at 60° C. for 40 min. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (11.2 g). The obtained brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (4.8 g) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH:21]=O)[CH:16]=[CH:17][C:18]=1[F:19].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][C:18]([F:19])=[C:13]([F:12])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=CCc1ccc(F)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a solution of tert-butyl-N-(2-aminoethyl)carbamate (718 mg, 4.5 mmol) in MeOH (40 mL) at 0° C., under nitrogen, was added (3,4-difluorophenyl)acetaldehyde (0.7 g, 4.5 mmol) in MeOH (10 mL), acetic acid (0.78 mL, 13.5 mmol) and sodium cyanoborohydride (564 mg, 9.0 mmol). After stirring at 0° C. for 15 min the cooling bath was removed and the mixture stirred at room temperature for 3 h. Saturated K2CO3 solution (50 mL) was added and the mixture stirred for a further 15 min. The solvents were removed in vacuo and the residue partitioned between water (50 mL) and EtOAc (2×50 mL). The combined organic layers were dried (Na2SO4), and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (90:10:1) to give the amine (473 mg, 35%) as a yellow oil. 1H NMR (250 MHz, CDCl3) δ 1.44 (9H, s), 2.72-2.78 (4H, m), 2.83-2.90 (2H, m), 3.18-3.28 (2H, m), 4.87 (1H, br s), 6.87-7.13 (3H, m). MS (ES+) (301, M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.C(N(CC)CC)C.[CH:34](OCC)=[O:35]>C(OCC)(=O)C>[CH:34]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)=[O:35]
Reactant: CCOC=O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=CN1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (450 mg, 1.19 mM) and triethylamine (156 mg, 1.56 mM) were heated under reflux for 48 hours in ethyl formate (20 ml). The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water and brine. Drying (sodium sulfate) and evaporation gave a gum which crystallised on trituration with diethyl ether to give the desired product (358 mg).
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.Br[CH:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[CH2:21]([O:20][C:18]([CH:17]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[CH3:22]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: Oc1ncn(-c2ccccc2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCCCC(Oc1ncn(-c2ccccc2)n1)C(=O)OCC
Yield: 27.7 %

Procedure:
The process was carried out as shown in Example 7 above, beginning with 1.4 g of sodium, 30 ml of methanol, 150 ml of dimethylsulfoxide, 10 g of 3-hydroxy-1-phenyl-1,2,4-1H-triazole and 13.8 g of ethyl 2-bromohexanoate. The product was distilled at 205° and 1 mm of mercury to obtain 5.2 g of the desired product, an oil.