Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:31][O-:32].[Na+]>CO.CS(C)=O>[CH3:31][O:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (35 mg, 0.075 mmol) was reacted with sodium methoxide (0.5 M in methanol, 1.0 mL, 0.488 mmol) in a mixture of methanol (4 ml) and DMSO (0.5 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (15 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=O>ClCCl>[Cl:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21

Procedure:
A modification of the method described in Part E of Example 1 was used to treat tert-butyl 2-[(3-aminoquinolin-4-yl)amino]ethylcarbamate (15.65 g, 51.76 mmol) with triethylamine (10.82 mL, 77.64 mmol) followed by chloroacetyl chloride (4.5 mL, 57 mmol). The reaction was carried out in dichloromethane (60 mL). After the reaction mixture was filtered, the filtrate was washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure to provide tert-butyl 2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as an amber-colored solid, which was combined with material from two other runs for use in the next step.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:14][O:13][C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CO[C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
6.7 g (22 mmol) of tert.-butyl N-(trans-1-benzyl-4-methoxypyrrolidin-3-yl)carbamate are hydrogenated in 150 ml of methanol on 2 g of palladium-on-active charcoal (10% of Pd) under 100 bar at 100° C. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:10](OCC)=[O:11].C(O)C>O.CCCCCC>[OH:11][CH:10]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: CCOC=O
Reactant: O=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCCCCC
Product: O=C1CCCCC1=CO
Reaction time: 20 h
Yield: 126 %

Procedure:
Cyclohexanone (200 grams, 2.0 moles) is added dropwise over a period of 2.75 hours to a stirred mixture of sodium hydride (50% oil dispersion, 105 grams, 2.1 moles), ethyl formate (200 grams, 2.7 moles), anhydrous ethanol (5 ml) and hexane (3500 ml) at 20° C. under nitrogen. Stirring is continued at room temperature for an additional 20 hours at which time a quantity of water sufficient to dissolve the reaction mixture is added. The layers are separated and the organic phase is washed twice with 5% aqueous sodium hydroxide. The combined aqueous phases are acidified with 25% aqueous sulfuric acid, and extracted three times with hexane. The organic phase is then washed twice with water, and distilled through a 4" vigreaux column at a 1:1 reflux take off ratio from 1 g hydroquinone to yield 318 g (63% theory)2-hydroxymethylenecyclohexanone. Bp 47°-48° C. @ 0.5 mm.
Reaction SMILES: [OH:1][CH:2]([CH:32]([CH3:34])[CH3:33])[CH2:3][C@@H:4]1[CH2:9][C@H:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:7][CH2:6][C@@H:5]1[NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH:12]([N:10]([CH3:11])[C@@H:8]1[CH2:7][CH2:6][C@H:5]([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[C@H:4]([CH2:3][C:2](=[O:1])[CH:32]([CH3:34])[CH3:33])[CH2:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the isomeric mixture of N-(2-((1S,2S,4R)-2-(2-hydroxy-3-methylbutyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (34 mg; see Examples 11p and 11q) in 3 ml of anhydrous CH2Cl2 were added excess amounts of powdered 4A molecular sieves and pyridinium dichromate, and the mixture was stirred for 2 hours at room temperature. After addition of about 15 ml of EtOAc it was filtered through a plug of Celite, and evaporated to give an oily residue, which was purified by chromatography (silica gel, CH2Cl2 then 1:9:90 cNH4OH-MeOH—CH2Cl2) to give N-(2-((1S,2S,4R)-4-(isopropyl(methyl)amino)-2-(3-methyl-2-oxobutyl)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide as an amorphous solid. MS found: (M+H)+=484.3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1([NH2:7])[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccn2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccccn2)CCC1
Reaction time: 6 h
Yield: 38.5 %

Procedure:
Crude (1-pyridin-2-yl-cyclobutyl)-carbamic acid tert-butyl ester (7.0 g, 5.64 mmol) was dissolved in DCM (20 mL) and TFA (20 mL) was added dropwise. After 6 h, the reaction was concentrated in vacuo and partitioned between DCM (100 mL) and water (20 mL). The aqueous layer was extracted with DCM (2×50 mL). The aqueous layer was then concentrated in vacuo. The brown oil was dissolved in water (3 mL) and purified via Mass-directed reverse phase HPLC purification which yielded 322 mg of 1-pyridin-2-yl-cyclobutylamine as a formic acid salt (yellow solid), m/z=149.5 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
2-Amino-4,6-dichloropyrimidine (3.28 g, 20.0 mmol), 4-nitrophenol (2.78 g, 20.0 mmol), and potassium carbonate (4.15 g, 30.0 mmol) were heated and stirred in dimethylformamide (20 ml) at 100° C. for 3 hours. After returning the reaction solution to room temperature, it was poured into ice water (100 ml) and the precipitated crystals were filtered out, washed with water and blow-dried to obtain the title compound (4.93 g, 18.5 mmol, 92%) as colorless crystals.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]1([C:14](=[O:16])[CH3:15])[CH2:13][CH:12]=[CH:11][CH2:10]1>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:14]([CH:9]1[CH2:13][CH:12]2[CH:11]([CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)C1CC=CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CC(C(C)=O)CC21
Reaction time: 11 h

Procedure:
A solution of ethyl diazoacetate (0.266 mL, 2.179 mmol) in dichloromethane (6 mL) was added over 6 hours via syringe pump to a solution of 1-(cyclopent-3-en-1-yl)ethanone (200 mg, 1.816 mmol) and rhodium(II) acetate dimer (16.1 mg, 0.036 mmol) in dichloromethane (6 mL). After an additional 11 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-30% ethyl acetate/hexanes) to afford ethyl 3-acetylbicyclo[3.1.0]hexane-6-carboxylate. MS ESI calc'd. for C11H17O3 [M+H]+ 197. found 197.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.[Li]CCCC.[P:22](Cl)([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][P:22]([C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:27][CH2:28][CH3:29])=[O:23])[CH3:26]
Reactant: C#Cc1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(C#Cc1ccccc1)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of phenylacetylene (1 mmole) in anhydrous THF (5 mL) was treated with TMEDA (1.2 mmole) followed by n-BuLi (1.2 mmole) at −78° C. After 30 min the reaction was treated with diethyl chlorophosphate, and the resulting solution was stirred at −78° C. for 1 h. The reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave 1-diethylphosphono-2-phenylacetylene as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([Br:28])=[CH:23][CH:24]=3)[CH2:19]2)[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][CH:18]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH3:17])[CH2:19]2)=[CH:24][CH:23]=1
Reactant: CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(Br)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C1CCNCC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (347 g, 0.77 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min., and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (203 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13].N([O-])=O.[Na+]>C(OCC)(=O)C>[N+:12]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Commercially available 4-t-butyl phenol (30 g, 0.2 mole) was dissolved in 200 mL ethyl acetate in a 600-mL round-bottomed flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture was treated with nitric acid (13 mL, in 13 mL water) dropwise over 10 min and then a catalytic amount of NaNO2. After 45 min the reaction was washed with excess 1N HCl and the organic layer was dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) was dissolved in 100 mL ethyl acetate and placed into a Parr bottle with a teaspoon of 10% Pd/C. The mixture was placed on a hydrogenator under 50 psi hydrogen with agitation for 1 hr. The catalyst was filtered off through celite, and the ethyl acetate was stripped off under vacuum. The material crystallized with the addition of about 200 mL heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[Li]C(CC)C.C1CCCCC1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C@:32]2([OH:38])[C:33]3[N:34]([CH:35]=[N:36][CH:37]=3)[C@@H:30]([C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[F:21])[CH2:31]2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1C
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc([C@@]2(O)C[C@H](c3ccc(C#N)cc3F)n3cncc32)cc1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of 4-bromo-1,2-dimethylbenzene (77 mg, 0.42 mmol) in THF (1 mL) at −78° C. was added a solution of 1.4 M s-BuLi in cyclohexane (0.33 ml, 0.46 mmol). The crude was warmed to −40° C. and stirred between −40° C. and −30° C. for 1 hr. The crude was cooled to −60° C. A solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) was added. The crude was stirred at −60° C. for 1 hr. The crude was warmed to room temperature in 4 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 7.8 mg of the entitled product as the major diastereomer. MS 348.1 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 3H), 2.20 (s, 3H), 2.91 (dd, 1H), 3.29 (dd, 1H), 5.71 (d, 1H), 6.87 (s, 1H), 7.07 (d, 1H), 7.10-7.20 (m, 2H), 7.21 (s, 1H), 7.34 (d, 1H), 7.36 (s, 1H), 7.39-7.43 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH2:20]([NH2:22])[CH3:21]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:22][CH2:20][CH3:21]
Reactant: CCN
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Solvent: CO
Product: CCNc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 79 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 322 mg of 70% aqueous ethylamine and 25 ml of methanol were treated in the same manner as Example 2, whereby 255 mg (yield 79%) of 9-(2,6-dichlorobenzyl)-6-ethylaminopurine was obtained as needles melting at 222°-223° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH3:31][NH2:32]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22](=[O:23])[NH:32][CH3:31])[CH:20]=2)=[O:12])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCC(=O)N2c2cccc(C(=O)O)c2)no1
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)c1cccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)c1

Procedure:
To a stirred solution of 3-[(S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-benzoic acid (75 mg, 0.2 mmol) in dichloromethane (1 mL) 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (42 mg, 0.22 mmol) is added at room temperature. After 5 minutes methylamine (0.5 mL of 2 M solution in tetrahydrofuran, 1 mmol) is added. After 2 h solvent is removed in vacuo and the crude is purified by chromatography over silica gel eluting with methanol/dichloromethane to give the title compound as a white solid, ESI m/z 385 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[NH:11]S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH3:24]CN(C(C)C)C(C)C.C1(S)C=CC=CC=1>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][N:7]=1)[N:11]=[CH:24][CH:2]=[C:1]2[OH:3]
Reactant: CC(=O)c1cc(Cl)ncc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccnc2cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide (1.0 equiv.), dimethylformamidedimethylacetal (4.8 equiv.) and DIEA (4.8 equiv.) in DMF (0.15 M) was heated under Ar at 110° C. for 96 hours. Upon cooling, thiophenol (4.9 equiv.) was added and the solution was stirred at rt for 15 hours. The volatiles were removed in vacuo and following silica gel purification (0-1.5-3-5% MeOH/CH2Cl2) 6-chloro-1,7-naphthyridin-4-ol was obtained (55%). LC/MS=180.9/182.9 (M+H), LC=1.41 min
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:27]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:26])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Reactant: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(F)cc2F)cc1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 1.58 g of 6-[[(4-butylphenyl)-methyl]amino]-1-hexanol and 1.5 g of phenyl-N-(2,4-difluorophenyl)carbamate in 40 ml of toluene was heated at reflux for 5 hours. The reaction mixture was cooled and allowed to stand at room temperature for 16 hours. The solution was washed with 3N aqueous hydrochloric acid, brine, 1N aqueous sodium hydroxide and brine again, then was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a yellow oil. The oil was treated by preparative high pressure liquid chromatography and gave 0.93 g (37%) of the desired product as a colorless oil.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:16]=[C:15]3[S:17][C:18]4[CH2:23][S:22][CH2:21][CH2:20][C:19]=4[C:14]3=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:12]=2[Cl:32])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:41])C=1.O>C(Cl)Cl>[N:1]1([CH2:10][C:11]2[N:16]=[C:15]3[S:17][C:18]4[CH2:23][S:22](=[O:41])[CH2:21][CH2:20][C:19]=4[C:14]3=[C:13]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C:12]=2[Cl:32])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(-c2c(Cl)c(Cn3cnc4ccccc43)nc3sc4c(c23)CCSC4)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2c(Cl)c(Cn3cnc4ccccc43)nc3sc4c(c23)CCS(=O)C4)cc1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of the compound obtained in Example 1 (800 mg) in methylene chloride (20 ml) was added m-chloroperbenzoic acid (70%, 400 mg) under ice cooling and then the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 2-[(1H-benzimidazol-1-yl)methyl]-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine (530 mg, 64%) from the eluates with ethyl acetate-methanol (20:1). It was recrystallized from THF-hexane. Colorless prisms. Melting point 233–235° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].[F:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>O1CCCC1>[F:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([OH:24])[CH:10]([CH:11]([CH3:13])[CH3:12])[C:9]([O:15][CH2:16][CH3:17])=[O:14])=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
Lithium diisopropylamide (22.2mL of 1.8M solution, 40 mmol) was added to a solution of ethyl isovalerate (5.2g, 40 mmol) in 40 mL of tetrahydrofuran at -40° C. After stirring for 0.5 hours and cooling to -70° C., 4,4'-difluorobenzophenone (4.36 g, 20 mmol) was added and the mixture stirred for 3 hours during which time the temperature was allowed to warm to -20° C. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 5.3 g of the title product; m.p. =118°-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13](=O)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>CN(C=O)C>[NH2:8][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])=[N:9][C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=1
Reactant: CCOC(=O)C(N)C(=N)N
Reactant: O=C(C(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 600 h

Procedure:
To a solution of amino-carbamimidoyl-acetic acid ethyl ester (Int E2)(1.25 g, 8.61 mmol) in DMF (5 ml) was added 1,1,1,4,4,4-hexafluorobutane-2,3-dione (5 g, 25.8 mmol) and the mixture was stirred at RT for 25 days. The yellow suspension was partitioned between EtOAc (50 ml) and water (50 ml) and the organic portion was washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by mass directed LC-MS eluting with MeCN/Water/0.1% TFA. The clean fractions were poured into EtOAc (50 ml) and washed with saturated NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound; 19F NMR (400 MHz, DMSO-d6): Peak 1 at −62 ppm, peak 2 at −64.6 ppm
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)C>[B:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12]2)=[N:7][CH:6]=1)([OH:10])[OH:9]
Reactant: O=C(O)C1CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 80 °C
Yield: 60.3 %

Procedure:
2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in ethanol (25 mL). Triethylamine (1.78 mL, 12.6 mmol) was added and the mixture was heated at 80° C. for 16 h. The reaction mixture was cooled and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 7.6 mmol, 60%) as a white solid. δH (d6-DMSO) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.