Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(F)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g--see Preparation 3), 4-fluorophenethyl bromide (0.22 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and 10% aqueous potassium carbonate (20 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.259 g.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[C:28]([N:2]2[CH2:3][CH:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=3)[CH2:5]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Reactant: Clc1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1N1CC(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
To a solution of 2-azetidin-3-yl-quinoline hydrochloride (1.70 g, 7.75 mmol) in DMF (30 mL) at room temperature was added Cs2CO3 (5.2 g, 16 mmol) and 2,3-dichloro-pyrazine (1.3 g, 9.0 mmol). The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.30 g, 4.4 mmol, 58% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O-])(O)=O.[Na+]>CO>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)OC
Yield: 95 %

Procedure:
a-Benzylacrylic acid (1.00 g, 6.17 mmol) in methanol (20 ml) was treated with BF3 ·Et2O (2 ml). The mixture was heated to reflux for 14 h, cooled, and poured into saturated NaHCO3 solution. Extraction with ether followed by drying over Na2SO4 and evaporation afforded 1.03 g (95%) of a mobile oil. 1H NMR (CDCl3) δ 7.17-7.35 (m, 5H), 6.23 (m, 1H), 5.47 (m, 1H), 3.74 (s, 3H), 3.63 (s,2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[S:34])[NH2:33])[CH2:27][CH2:26]1>>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:18])[C:7]2[CH:6]=[C:5]([C:3]3[N:33]=[C:32]([N:28]4[CH2:29][CH2:30][CH2:31][CH:25]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][OH:19])[CH2:26][CH2:27]4)[S:34][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: NC(=S)N1CCCC(NCCCCO)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 508 mg (1.15 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and the product from step c. The purification was carried out by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].Br[C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29].Cl>CN1CCCN(C)C1=O.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(Br)C(N)=O
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CC(C)(C(N)=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reaction time: 18 h

Procedure:
4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg) was dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (1.5 ml) with stirring and sodium hydroxide (0.158 g) was added at ambient temperature and the mixture stirred for 15 minutes. 2-Bromo-2-methylpropanamide (0.5 g) was added and the mixture was stirred vigorously for 18 hours at ambient temperature under a water-free atmosphere, then further 2-bromo-2-methylpropanamide (0.15 g) was added and stirred for a further 24 hours. Water (3 ml) was added to the reaction mixture together with dilute hydrochloric acid (5M) to adjust the pH to 0. The suspension was added to water (60 ml) and the mixture left to stand for 18 hours at ambient temperature. The solid was collected by filtration, washed well with water and dried under high vacuum at 50° C. The solid was purified by preparative HPLC (reverse phase). Appropriate fractions were collected and combined and extracted with dichloromethane. Evaporation of the dichloromethane gave 2-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methylpropionamide, m.p. 227-228° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[C@H:15]([CH3:20])[CH2:16][NH:17][C:18](=[O:19])[C:10]3=[CH:9][C:8]=2[CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:20][C@H:15]1[N:11]2[C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:7][C:8]=3[CH:9]=[C:10]2[C:18](=[O:19])[NH:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(OCCCCl)ccc3n21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C[C@@H]1CNC(=O)c2cc3cc(OCCCN4CCCCC4)ccc3n21
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 2, from (R)-8-(3-chloro-propoxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, piperidine (commercially available), potassium carbonate and potassium iodide, to give the desired product as a light yellow solid (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C
Reaction time: 1.33 h
Yield: 97 %

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.856 g, 2.77 mmol, Preparation #1, Step A) in THF (20 mL) at about −78° C. was added sec-BuLi (4.35 mL1, 6.10 mmol) dropwise. The reaction was stirred at −78° C. for about 80 min. To the mixture was added ethyl chloroformate (0.665 mL, 6.93 mmol. The flask was removed from the cooling bath and stirred for about 70 min at rt. The mixture was quenched by the addition of a saturated aqueous NH4Cl (5 mL). EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×15 mL), and the combined organic layers were washed with brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography (40 g Redi-Sep™ silica column) eluting with 0-10% EtOAc in heptane to give ethyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.02 g, 97%): 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 7.69 (d, J=3.6, 1H), 6.72 (dd, J=68.4, 3.5, 1H), 4.34 (q, J=7.0, 2H), 1.86 (dt, J=15.0, 7.5, 3H), 1.34 (t, J=7.1, 3H), 1.05 (d, J=7.5, 18H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][CH2:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18]>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:15]([C:14](=[O:20])[CH2:13][CH3:12])[C:16](=[O:19])[CH2:17][CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)CC(=O)CC
Product: CCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CC

Procedure:
The procedure described in Example 1 was repeated by using 1.5 g of 4-nitrobenzaldehyde and 2.0 g of 3,5-heptanedione. Yield 1.7 g, yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[N:3]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>CC(=O)OCC.C([O-])(O)=O.[Na+]>[C:27]1([O:26][C:24](=[O:25])[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:4]3[N:3]=[C:2]([Cl:1])[C:7]([S:8][CH3:9])=[C:6]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:5]=3)=[CH:17][CH:18]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSc1c(Cl)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (915 mg, 2.717 mmol.) in EA (20 ml) and NaHCO3 (20 ml) the reaction was stirred at r.t. then added dropwise to slurry of phenyl chloroformate (851 mg, 0.543 mmol, 2.0 eq) at reaction for 2 hr. The reaction mixture was partitioned between EA/NaHCO3, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was recrystallized by (Hexane/EtOAc) to give a pale yellow product of 1056 mg (85.1%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)(=O)C.C(O)(=[O:15])C>>[CH:10]([C:9]1[O:12][C:6]([C:5]([OH:4])=[O:15])=[CH:7][CH:8]=1)=[O:11]
Reactant: CC(=O)OCc1ccc(C=O)o1
Reactant: CC(=O)O
Product: O=Cc1ccc(C(=O)O)o1

Procedure:
5-HMF feed is oxidized with elemental O2 in a multi-step reaction to form FDCA with 5-formyl furan-2-carboxylic acid (FFCA) as a key intermediate eq 1. Oxidation of 5-(acetoxymethyl)furfural (5-AMF), which contains an oxidizable ester and aldehydes moieties, produces FDCA, FFCA, and acetic acid, eq 2. Similarly oxidation of 5-(ethoxymethyl)furfural (5-EMF) produces FDCA, FFCA, 5-(ethoxycarbonyl)furan-2-carboxylic acid (EFCA) and acetic acid, eq 3.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=O)C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:12]2[C:9]3=[CH:10][N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:3])[C:7]([OH:25])=[C:8]3[C:14]([CH3:15])=[C:13]2[CH3:16])=[CH:19][CH:20]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccc(F)cc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2cnc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-1-(4-fluoro-benzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 372 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].C(Cl)Cl.[OH2:14]>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH:10]=[O:14]
Reactant: O
Reactant: COc1cccc(C)c1C
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(C)c1C=O
Temperature: 25 °C

Procedure:
A mixture of commercially available 1-methoxy-2,3-dimethylbenzene (10.000 g; 73.40 mmol), copper(II) sulfate pentahydrate CuSO4.5H2O (18.334 g; 73.40 mmol), and potassium peroxodisulfate K2S2O8 (59.547 g; 220.00 mmol) in MeCN (250 ml) and water (250 ml) was heated at reflux, under nitrogen, for 30 min. After cooling to rt, DCM was added and the aq. layer was further extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=9/1) afforded 2-methoxy-6-methylbenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.70 min.; no ionisation.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5]([CH3:7])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5](=[N:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH3:7]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)C(=NO)C(=O)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C(C)C(=NO)C(=O)N(C)C)cc1

Procedure:
a mixture of 142 parts of N,N-dimethyl-2-hydroxyiminoacetoacetamide (a compound of Formula III), 1200 parts of toluene, 123 parts of p-anisidine and 1 part of p-toluenesulfonic acid was refluxed overnight in a flask fitted with a Dean-Stark distilling trap and water condenser. Eighteen parts of water were removed in this manner. On cooling, a heavy slurry of solid product precipitated. This was filtered and washed with butyl chloride thereby providing a product which melted at 201.5°-203° C. Recrystallization from acetonitrile gave 151 parts of N,N-dimethyl-2-hydroxyimino-3-(4-methoxyphenylimino)butyramide (a compound of Formula II) as a yellow solid, m.p. 204°-205.5° C.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Cl:14][C:15]1[CH:16]=[C:17]([C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[C@@H:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)[OH:25]
Reactant: CCCCCC
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.5 mL, 3.0 mmol) was added to a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid (497 mg, 2.66 mmol) in benzene (2.6 mL)-methanol (1.3 mL) under cooling with ice. Then, the ice bath was removed and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (533 mg, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:34])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH2:33])=[N:31][O:30][N:29]=2)=[CH:13][CH:12]=1)(C)(C)C.[ClH:37].C(OC(C)C)(C)C>O1CCOCC1>[ClH:37].[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:34])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH2:33])=[N:31][O:30][N:29]=2)=[CH:15][CH:16]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: NCC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.045 g of [(4-{2-[2-(4-amino-furazan-3-yl)-benzoimidazol-1-yl]-acetyl}-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.09 mmol; 1 eq.) in 0.5 mL of 1,4-dioxane are added dropwise 0.11 mL of a 4M HCl solution in 1,4-dioxane (0.44 mmol; 5 eq.) at room temperature. The reaction mixture is stirred for 2 h at room temperature. Then, 5 mL of diisopropylether are added and the resulting suspension is filtered, washed with diisopropylether (2×2 mL) and dried under reduced pressure to give 0.04 g of crude material. The crude solid is subjected to MCI gel column chromatography eluting with a mixture water/acetonitrile (85/15 to 70/30) containing 0.05% of HCl, to afford 0.014 g of the desired product as an orange powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:24])[C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[N:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:26](=[O:27])[NH:25][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=2)[CH:3]=1)[C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])=[N:17][C:12]2=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CN(c1cccc(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of N-{5-[(3-aminophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.295 mmol) produced in Example 8(x) in N,N-dimethylformamide (1.0 mL) was added 1-isocyanato-4-(trifluoromethoxy)benzene (53 μL, 0.354 mmol), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration, and recrystallized from hexane/tetrahydrofuran to give the title compound (101 mg, 63%) as a colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:12])[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:12][CH2:25][CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCN
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and isoamylamine (0.24 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(isoamyl)-(2-(naphthalen-2-yloxy)-ethyl)amine, solid, m.p. 91° C., (yield 0.51 gm, 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[NH4+]=S>CO>[NH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Solvent: CO
Product: Nc1cc(CO)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of 3,5-dinitrobenzyl alcohol (129.1 g, 0.65 mol; from step (i) above) in MeOH (1500 mL) at reflux was added ammonium sulfide (450 mL, 442.9 g of 20 wt % in H2O, 1.30 mol) over 45 min. The resulting heterogeneous mixture was refluxed for 2 h and stirred at 25° C. for 18 h. The solution was filtered through a pad of Celite, the filtrate was acidified with 2N HCl and the MeOH distilled off in vacuo. The remaining acidic aqueous solution was washed with Et2O (3×) and basified with 6N NaOH. The basic aqueous solution was extracted with Et2O (4×). The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 95.8 g (88%) of the sub-title compound as an orange solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[OH:13][C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
A solution of methyl 4-methoxysalicylate (50 g) in glacial acetic acid (700 ml) was treated dropwise with concentrated nitric acid (50 ml) over 15 minutes. After stirring for 2 hours, then standing at room temperature for 18 hours, the mixture was treated with a further aliquot of concentrated nitric acid (10 ml) then stirred for 6 hours. The reaction mixture was diluted with ice then poured into water (1000 ml), then filtered. The solid was dried then subjected to flash chromatography on silica eluting with a mixture of toluene and dichloromethane (2:1, v/v) to give the title compound as a white solid, m.p. 185-187° C.
Reaction SMILES: [C:1]([S:5](/[N:7]=[C:8](/[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)\[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Mg]Br.C(OCC)C>C(Cl)Cl>[C:1]([S:5]([NH:7][C@@:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:26])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: COC(=O)C(C)(C)CC/C(=N\S(=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC[C@](C)(NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of methyl (5E)-5-[(tert-butylsulfinyl)imino]-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate (342 mg, 0.920 mmol) in CH2Cl2 (6 mL) at 0° C., was added dropwise over five minutes methyl magnesium bromide as a 3M solution in diethyl ether (0.61 mL, 1.83 mmol). After 15 minutes the reaction was determined to be complete by LCMS analysis. The reaction was quenched by the dropwise addition of 1M HCl (5 mL), followed by 5 mL of water. The aqueous layer was extracted once with CH2Cl2 (10 mL) and the organics were combined and washed once with brine (15 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 55:45, to give the title compound. MS: m/z=390 (M+1).