Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:22])[C:13]([CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=2)=[C:12]3[C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[F:63][C:64]([F:70])([F:69])[S:65]([NH2:68])(=[O:67])=[O:66].C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[O:34][CH2:33][C:13]1[N:14]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([NH:68][S:65]([C:64]([F:70])([F:69])[F:63])(=[O:67])=[O:66])=[O:28])[CH:25]=2)[C:15]2[C:11]([C:12]=1[C:45]([N:47]1[CH2:48][CH2:49][CH2:50][CH2:51]1)=[O:46])=[CH:10][C:9]([NH:8][C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:7])=[CH:17][CH:16]=2
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21)Nc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21)Nc1cccc(C(=O)NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
The compound of Example 55 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), trifluoromethanesulfonamide (1.2 eq) followed by anhydrous THF (0.04 M) and the reaction mixture was then stirred at 25° C., overnight. Worked up with ethyl acetate/water followed by washing the organic layer with 1N HCl, saturated bicarbonate and brine. Trituration with CH2Cl2/hexane (8:2) afforded the desired product in 84% yield.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:15]1[CH:25]=[CH:24][C:18]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:16]=1)(=[O:14])[CH3:13]>ClCCl>[C:12]([C:15]1[CH:25]=[CH:24][C:18]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:17]([S:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[O:9])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(S(=O)c2ccc(F)cc2F)c1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of m-chloroperbenzoic acid (80%; 0.76 g) in dichloromethane (12 ml) was added dropwise to a stirred solution of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1.2 g) in dichloromethane (12 ml) at 5° to 10° C. The solution was stirred for 1 hour at the same temperature, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated. The oily residue (0.9 g) was crystallized from ethanol to give crystals of 4'-acetyl-2'-(2,4-difluorophenylsulfinyl)methanesulfonanilide (0.73 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:21]([O:20][C:18]([NH:17][C@H:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]([CH:29]=[CH:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:8][CH:9]=2)[CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl trifluoromethanesulfonate (500 mg), ethyl acrylate (179 μl), triphenylphosphine (22 mg), palladium acetate (9.3 mg) and triethylamine (250 μl) were allowed to react for 6 hours at 90° C. and for 5 hours at 100° C. with stirring. Ethyl acrylate (97 μl), triethylamine (125 μl) and bis(triphenylphosphine)palladium(II) dichloride (27 mg) were added to the reaction mixture, followed by reaction for 11 hours at 100° C. with stirring. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 N hydrochloric acid and 0.5 M aqueous phosphate buffer solution (pH 7) sequentially, and dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo. Purification by medium pressure liquid column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=20/1) and sequential recrystallization from diisopropyl ether of the residue gave ethyl (S)-3-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]acrylate (252 mg) having a melting point of 99-100° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.CO.[BH4-].[Na+]>O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 117 parts of (4-trifluoromethylphenyl)methanone in 136 parts of methanol there were added portionwise 13.1 parts of sodium tetrahydroborate under a nitrogen atmosphere, while cooling on ice. After stirring for 18 hours at room temperature, the reaction mixture was poured into water which was acidified with HCI (20%). The product was extracted with 2,2'-oxybispropane (2×) and the combined extracts were washed with water, dried, filtered and evaporated, yielding 130 parts (100%) of 4-(trifluoromethyl)benzenemethanol (interm. 10).
Reaction SMILES: [Cl-].C(C[P+](C)(C)C)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:27]=[S:28]1(=[O:56])[CH2:33][CH2:32][N:31]([C:34]([C:36]2[NH:37][C:38]3[C:43]([CH:44]=2)=[CH:42][C:41]([C:45]([N:47]2[CH2:52][CH2:51][N:50]([CH:53]([CH3:55])[CH3:54])[CH2:49][CH2:48]2)=[O:46])=[CH:40][CH:39]=3)=[O:35])[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[CH2:19]([N:37]1[C:38]2[C:43](=[CH:42][C:41]([C:45]([N:47]3[CH2:48][CH2:49][N:50]([CH:53]([CH3:54])[CH3:55])[CH2:51][CH2:52]3)=[O:46])=[CH:40][CH:39]=2)[CH:44]=[C:36]1[C:34]([N:31]1[CH2:32][CH2:33][S:28](=[O:27])(=[O:56])[CH2:29][CH2:30]1)=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OCc1ccccc1
Agent: C[P+](C)(C)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
To the suspension of 105 mg (0.70 mmol) (cyanomethyl)trimethylphosphonium chloride (prepared according to Tetrahedron Lett. 1996, 37 (14), 2459-62) in 1 mL toluene, 1.39 mL (0.70 mmol; 0.5M solution in toluene) potassium bis(trimethylsilyl)amide was added. After 10 min., 71 μL (74 mg, 0.70 mmol) benzylalcohol and 0.15 g (0.35 mmol) [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1) were added and the suspension was stirred for 1 h at reflux temperature. After cooling to room temperature the reaction mixture was evaporated to dryness, the residue was taken up in dichloromethane, filtered and the filtrate was evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane:methanol:ammonia (19:1:0.1 v/v) as eluant to give 118 mg (65%) of the desired compound as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31][CH2:32][CH2:33]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][S:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCSc1ccc2ccccc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCSc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthylthio)ethanol (1.4 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 0.55 g of 4-[[2-(2-naphthalenylthio) ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 63°-65° C.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C(Cl)Cl>[P:1]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=Cc1ccccc1O
Reactant: CCCSP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Oc1ccccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of O-ethyl S-propyl chlorothiophosphate prepared in Example 1 was cooled to 10° C. and triethylamine (1.629 grams; 0.016 mole) was added. A solution of 2-hydroxybenzaldehyde (1.95 grams; 0.016 mole) in methylene chloride (5 ml) was slowly added to the mixture while maintaining the temperature at about 0° C. After this addition was completed the temperature of the reaction mixture was allowed to rise to room temperature and stirring was continued for a period of one hour. After this time the reaction mixture was transferred into a separatory funnel and methylene chloride (100 ml) was added. The resulting solution was washed twice with water (100 ml), twice with aqueous sodium hydroxide (0.1 N; 50 ml) and again twice with water (100 ml). The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under vacuum in a rotary evaporator leaving a light orange oil as the residue. This oil was placed under high vacuum for a period of one hour to yield the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Mg]Cl.[O:11]=[C:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[Mg+2].[Cl-]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:12]1([OH:11])[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: Fc1ccc(F)c([Mg]Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(O)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In step 6A-1, (2,5-difluorophenyl)magnesium chloride (6-1) was added drop-wise to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (6-2) (9.6 g, 52 mmol) in THF under argon at −78° C. A maximum of 5 mL aliquots was used to minimize the temperature increase of the magnesium chloride reagent. The resulting solution was then stirred at −78° C. for one hour. The solution was then warmed to room temperature and quenched with concentrated HCl (4 mL). The solvent was then removed using a rotary evaporator resulting in a light yellow residue. The residue was then reconstituted in ethyl acetate and extracted with brine (3×150 mL). The organic layer was then dried using sodium sulfate. The ethyl acetate was removed yielding tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (6-3) as a light yellow oil. m/z=300 [M+1] The product was used without further purification.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:29])[C@H:21]1[C@H:25]2[CH2:26][CH2:27][C@@H:22]1[C@H:23]([OH:28])[CH2:24]2)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C([O:32][C:33](=O)[C:34]([OH:45])([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCOCC>[C:6]([Si:3]([CH3:4])([CH3:5])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:29])[C@H:21]1[C@H:25]2[CH2:26][CH2:27][C@@H:22]1[C@H:23]([O:28][C:33](=[O:32])[C:34]([OH:45])([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[CH2:24]2)([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(CCCCCCCCCO[Si](C)(C)C(C)(C)C)[C@H]1[C@H]2CC[C@@H]1[C@H](O)C2
Reactant: CCOC(=O)C(O)(c1cccs1)c1cccs1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN(CCCCCCCCCO[Si](C)(C)C(C)(C)C)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Temperature: 80 °C

Procedure:
Sodium hydride (254 mg, 60% suspension in mineral oil, 6.35 mmol) was added to a solution of (1S,2R,4S,7S)-7-{[9-(tert-butyldimethylsilanyloxy)nonyl]methylamino}-bicyclo[2.2.1]heptan-2-ol (1.01 g, 2.54 mmol) in dry toluene (20 mL) at 0° C. under a nitrogen atmosphere. As soon as the gas evolution subsided hydroxy-di-thiophen-2-yl-acetic acid ethyl ester (817 mg, 3.04 mmol) was added in portions, and when the gas evolution stopped the reaction mixture was heated at 80° C. on a preheated sand bath. After 2.5 h the reaction mixture was poured onto satd ammonium chloride (aq) and ether. The layers were separated, the aqueous layer extracted with ether, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to afford a light brown viscous oil. The crude product was purified by column chromatography over silica gel using a gradient of 1-40% ethyl acetate in DCM as eluent to afford the product as a very light brown viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[I:28]I.[OH-].[K+]>N1C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([I:28])=[CH:4][N:3]=1
Reactant: Nc1nccc2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1ncc(I)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12

Procedure:
As shown in the Scheme above, 1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea ((1), prepared as described in WO2005/10009), in a mixture of pyridine and tetrahydrofuran can be treated with iodine at room temperature, followed by treatment with potassium hydroxide at elevated temperature to provide 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2). Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be prepared by reacting 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2) with carbon monoxide gas in the presence of a catalyst such as but not limited to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, and a base such as but not limited to triethylamine. The reaction is typically performed under pressure and at an elevated temperature. Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be reacted with aqueous lithium hydroxide to provide 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4). The reaction is typically performed at elevated temperature in a solvent such as but not limited to tetrahydrofuran and methanol. 4-Amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4) can be reacted with N,N-diethyl-1,3-propanediamine in the presence of a coupling agent such as but not limited to 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, an auxiliary coupling reagent such as but not limited to 1-hydroxybenzotriazole hydrate, and a base such as but not limited to N-methylmorpholine to provide 4-amino-N-[3-(diethylamino)propyl]-3-(4-{[(3-fluorophenyl)carbamoyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (5). The reaction is typically performed in a solvent such as but limited to N,N-dimethylformamide.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1>CC(N(C)C)=O>[Br:11][C:12]1[CH:17]=[C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of benzyl alcohol (10 g), sodium hydride (4.44 g of a 50% w/w dispersion in meneral oil) and dimethylacetamide (180 ml) was stirred at ambient temperature for 1 hour; 1-bromo-3,5-difluorobenzene (10.65 ml) was added and the exothermic reaction mixture was stirred for 2 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluent. There was thus obtained, as a liquid, benzyl 3-bromo-5-fluorophenyl ether (19.5 g, 75%).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].Cl.[NH2:14][OH:15]>C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[N:14][OH:15])[NH2:12])=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(=NO)c1ccc(C(=O)O)cn1

Procedure:
Sodium (18 mmol) is added to a flask containing 20 ml of ethanol. After the sodium has dissolved, 3.8 mmol of 5-carboxy-2-cyanopyridine and 18 mmol of hydroxylamine hydrochloride are added, and the solution is refluxed for 5 h. After cooling, the resulting precipitate is filtered off and recrystallized from water; m.p.>300°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:33])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([O:33][CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH3:14])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cnc(OCC(C)C)c(Cl)c2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (250 mg, 0.965 mmol) in acetone (20.0 mL) were added potassium carbonate (267 mg, 1.93 mmol) and 5-chloro-6-isobutoxypyridin-3-ol (Preparation 1, 195 mg, 0.965 mmol) and the reaction mixture was heated at reflux for 16 hours, then allowed to cool to room temperature. The solvent was removed in vacuo to yield a yellow solid, which was partitioned between EtOAc (30.0 mL) and water (50.0 mL). The aqueous was further extracted with EtOAc (2×30 mL). The combined organics were washed with sodium hydroxide solution (1 M, 30 mL) then brine (50 mL), dried over sodium sulfate and the solvent was removed in vacuo to yield the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1COCC1.CO>[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[N:26]([CH3:1])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:21]
Reactant: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (3.9 g, 15 mmol) was added to a solution of sulfonamide 16-6 (4.5 g, 10 mmol) in THF (30 mL). To this solution was added a solution of diethyl azodicarboxylate (2.4 mL, 15 mmol) in THF/MeOH (10 mL/2.02 mL). A vigorous exotherm occurred and the reaction was stirred overnight at room temperature. The dark mixture was concentrated. The dark oily residue was purified by flash chromatography (40% EtOAc/hexanes) to give the desired product 16-7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: CC(C)CBr
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC(C)C

Procedure:
The title compound, MS: m/e=274.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 1-bromo-2-methylpropane.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:14][CH:13]=[CH:12][CH:11]=2)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:2][CH2:3][C:4]1[N:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(NC(=O)CCl)cnc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cccnc3c21
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl 3-({3-[(chloroacetyl)amino][1,5]naphthyridin-4-yl}amino)propylcarbamate hydrochloride (from Part E, approximately 57.6 mmol) in 3:1 ethanol/water (240 mL) was added 6 M aqueous potassium carbonate. The reaction mixture was stirred at room temperature for 1 hour, 40° C. for 1.5 hour, then at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (250 mL) and water (150 mL). The aqueous layer was extracted with dichloromethane (2×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 18.9 g of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propylcarbamate.
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CCl)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
SOCl2 (57 g, 0.48 mol) was added to a solution of methyl 6-(hydroxymethyl)picolinate 70 (40.0 g, 0.239 mol) (Chem. Eur. J. 2006, 12, 6393-6402) in dichloromethane (500 mL) at room temperature. The mixture was stirred at 40° C. for 1 h and sat. aq K2CO3 was added to adjust the pH to 9. The mixture was extracted with CH2Cl2 and the combined organics were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 71 (45 g).