Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([OH:6])[C:4]#[CH:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([O:6][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[C:4]#[CH:5]
Reactant: C#CC(O)C(C)(C)CCCC
Reactant: C1=COCCC1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(OC1CCCCO1)C(C)(C)CCCC
Temperature: 25 °C

Procedure:
To a solution of 23.1 g. (0.150 mole) of 4,4-dimethyl-1-octyn-3-o1 (Example 994) in 126 g. of freshly distilled dihydropyran is added 1 drop of phosphorus oxychloride and the solution is maintained at ambient temperature in a tightly stoppered flask for 20 hours. Five drops of triethylamine are then added and the mixture is evaporated in vacuo to an oil. The oil is chromatographed on 600 g. of silica gel and the product is eluted with 5% ethyl acetate in benzene yielding a colorless oil.
Reaction SMILES: Br.C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[CH2:14]Br)[N:8]=1)(=O)C.[NH2:17][C:18](=[N:20][C:21]([NH2:23])=[S:22])[NH2:19]>CO>[NH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[N:23]=[C:21]([N:20]=[C:18]([NH2:19])[NH2:17])[S:22][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: NC(=S)N=C(N)N
Reactant: CC(=O)NCc1cccc(C(=O)CBr)n1
Agent: Br
Solvent: CO
Product: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 42.4 %

Procedure:
A mixture of 2-(acetylaminomethyl)-6-bromoacetyl-pyridine hydrobromide (3.34 g) and diaminomethylenethiourea (1.01 g) in methanol (50 ml) was refluxed for 10 hours with stirring. The resulting precipitate was collected, dissolved in water (50 ml) and the solution was made basic with aqueous potassium carbonate. The separated product was collected and washed with water to give 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.90 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:22][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:35]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 0.075 g (0.25 mmol) of 5′-methyl-4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine in methylene chloride (5 mL) is added 0.050 mL (0.30 mmol) of triethylamine followed by 0.044 g (0.25 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then purified by preparative reverse phase HPLC to give 0.033 g (30%) of the title compound (3) as a white solid. [M+H]+=441.3.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([F:22])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([F:22])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(F)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O

Procedure:
(3-fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-carbamic acid t-butyl ester (1 ml) was put into 25 ml round-bottom flask and dissolved in methylenechloride. To the solution was added trifluoroacetic acid (1 ml) and stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield a brown crude liquid (236.7 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]#[N:21])[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](N)[CH2:25][NH2:26]>C(Cl)(Cl)Cl.C(O)C>[C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]4[NH:26][CH2:25][CH2:24][N:21]=4)[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: NCCN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1CC1=NCCN1
Temperature: -15 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
To a solution of (7-benzenesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetonitrile (0.156 g., 0.475 mmol) in 10 mL anhydrous chloroform was added ethanol (0.029 mL, 0.5 mmol), and the resulting solution was cooled in a water ice/acetone bath to −15° C. Hydrogen chloride gas was bubbled through the solution for 10 minutes, and the flask was sealed and kept at −15° C. for 18 hours. The reaction mixture was concentrated in vacuo and 0.5 Torr vacuum was applied to the residue for 2 hours. The crude imidate was dissolved in 5 mL anhydrous chloroform, and to this solution was added ethylene diamine (0.033 mL, 0.5 mmol) in 4 mL anhydrous chloroform and 5 mL ethanol. The resulting solution was stirred at room temperature for 3 hours, and was then concentrated in vacuo. The residue was purified by flash chromatography (30% “magic base” (6:1:0.1 methylene chloride:methanol:ammonia) in dichlormethane) to give 0.130 g (0.35 mmol, 74%) of 7-benzenesulfonyl-4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4H-benzo[1,4]oxazin-3-one as a clear oil. MS: 372 (M+H)+, mp: 113.7-116.0° C. (HCl salt).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=2)=[CH:5][CH:6]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[K+]>C(O)(=O)C.O>[C:15]([O:18][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[O:3][C:2]([Br:1])=[CH:6][CH:5]=2)[CH:8]=1)(=[O:17])[CH3:16]
Reactant: BrCc1cccc(-c2ccc(Br)o2)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1cccc(-c2ccc(Br)o2)c1
Reaction time: 19 h
Yield: 56 %

Procedure:
A stirred solution of 7.3 g (0.023 mol) of 2-bromo-5-(3-bromomethylphenyl)furan in 50 mL of acetic acid was cooled in an ice-water bath, and 3.4 g (0.035 mol) of potassium acetate was added. Upon complete addition, the reaction mixture was heated to reflux temperature and stirred for 19 hours. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL of water, then extracted with two portions of 150 mL each of chloroform. The combined extracts were washed with one portion of 150 mL of a saturated aqueous solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally with one portion of 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with hexane: chloroform (2:1). The appropriate fractions were combined to give 3.8 g of 3-(2-bromo-5-furanyl)phenylmethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Si:19]([O:9][CH2:8][CH2:7][N:6]1[C:2]([NH2:1])=[CH:3][CH:4]=[N:5]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccnn1CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCn1nccc1N)(c1ccccc1)c1ccccc1
Reaction time: 15 h
Yield: 96.1 %

Procedure:
To a suspension of 2-(5-amino-1H-pyrazol-1-yl)ethanol (2.07 g, 16.0 mmol) and 1H-imidazole (5.43 g, 79.8 mmol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (4.96 mL, 19.1 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (40 mL). The organic layer was washed with 1N HCl (10 mL), water (10 mL) and brine (10 mL), then concentrated to give crude desired product (5.62 g, 96.4% yield), which was used in the next step without purification.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:24][O:25]CC1C=CC=CC=1)[CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH2:23])=[N:17][C:18]=2Cl)C1C=CC=CC=1.C(O)=[O:34]>[Pd]>[OH:8][CH2:9][CH:10]([CH2:24][OH:25])[CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:34])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: Nc1nc(Cl)c2ncn(CCC(COCc3ccccc3)COCc3ccccc3)c2n1
Reactant: O=CO
Agent: [Pd]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reaction time: 0.75 h
Yield: 45 %

Procedure:
A solution of 4-(2-amino-6-chloropurin-9-yl)-2-benzyloxymethylbutyl benzyl ether (0.904 g, 2 mmol) in 25 ml of 80% aqueous formic acid was kept at 100° C. for 1h, palladium catalyst (10% on carbon, 0.40 g) was added, and the mixture was hydrogenated at room temperature and atmospheric pressure with efficient stirring for 45 min. After evaporation in vacuum to dryness the residue was heated to boiling with 50 ml of water, 1 ml of concentrated aqueous ammonia was added, the solution was boiled gently for a short while and then evaporated to dryness. Recrystallization from water afforded 0.23 g (45%) of 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine. M.p. 252°-262° C. (decomposition, slow heating) or 264°-265° (fast immersion of the capillary).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41]
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Yield: 51.9 %

Procedure:
A 48 mL sealed tube was charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.150 g, 0.529 mmol), 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.242 g, 0.793 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.0432 g, 0.0529 mmol), cesium carbonate (0.689 g, 2.11 mmol), 1,4-dioxane (3.62 ml, 42.3 mmol), and water (0.905 ml, 50.2 mmol), flushed with argon, sealed, then placed in a 80° C. oil bath for 5 hours. The contents were transferred to a flask and concentrated. The solid was triturated with water to give a red residue, which was purified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 51.9% yield) was isolated as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28]B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]3)=[CH:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH3:26]
Reactant: CC1=NN(c2ccc(Br)cc2)C(=O)C1
Reactant: COCOc1ccc(C=CB(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1ccc(C=Cc2ccc(N3N=C(C)CC3=O)cc2)cc1OC
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
2-(4-Bromo-phenyl)-5-methyl-2,4-dihydro-pyrazol-3-one (105 mg) was dissolved in DME (ethylene glycol dimethyl ether, 2 mL), then Pd(PPh3)4 (15 mg, 3% mol) was added. The air was exchanged with argon and the mixture was stirred for 10 min. A solution of 2-(3-methoxy-4-methoxymethoxy-phenyl)-vinyl-boronic acid (90 mg) in DME (1 mL) was added followed by sodium carbonate solution (2M, 0.75 mL). The mixture was stirred for 1 hour at 110° C. After partitioning with ethyl acetate and water and purification over silica gel eluting with 50% EtOAc in hexane gave 140 mg of 2-{4-[2-(3-methoxy-4-methoxymethoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro-pyrazol-3-one as an oily product, which was then hydrolyzed with conc. HCl in methanol. Evaporation of the solvent and purification over silica gel gave 2-{4-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-phenyl}-5-methyl-2,4-dihydro -pyrazol-3-one as a light yellow solid (90 mg). 1HNMR (CDCl3, 300 MHz): 7.74 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 6.77 (s, 3H), 6.48 (s 2H), 5.66 (s, 1H), 3.63 (s, 3H), 3.42 (s, 2H), 2.19(s, 3H) ppm. 13CNMR (CDCl3—CD3OD, 75 MHz): 170.48, 156.45, 146.04, 144.89, 136.70, 134.28, 129.97, 129.41, 128.00, 122.47, 118.46, 114.21, 111.14, 55.72, 43.10, 17.05 ppm. MS (m/z): 323 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15].F[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[N+:33]([O-:35])=[O:34].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[C:27]([O:26][C:24]([C:23]1[CH:31]=[CH:32][C:20]([O:12][C:11]2[C:10]([Cl:13])=[C:9]3[C:4]([CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[C:21]([N+:33]([O-:35])=[O:34])[CH:22]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Cl
Reactant: CC(C)(C)OC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Cl
Temperature: 80 °C
Yield: 104.1 %

Procedure:
A mixture of ethyl 6,8-dichloro-7-hydroxychroman-4-carboxylate (35 g, 120.22 mmol), tert-butyl 4-fluoro-3-nitrobenzoate (31.1 g, 128.93 mmol), K2CO3 (24.923 g, 180.33 mmol), and 1-methyl-2-pyrrolidinone (500 mL) was purged with Argon (bubbled through) for 15 minutes. The mixture was heated to 80° C. for 4 hours under Argon atmosphere. The mixture was cooled to ambient temperature and poured into 3 liters of water. The pH was adjusted to pH 2 by addition of concentrated HCl (4×10 ml). A solid precipitated out as HCl was added and gas evolution was observed. The crude mixture was filtered and the solid was dissolved in EtOAc (1 liter). The EtOAc solution was washed with 2N HCl solution (200 ml), water (2×200 ml), and brine (200 ml), dried over MgSO4, filtered, and concentrated to provide 64.1 g of the title compound as a dark solid (104%).
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[C:11]([CH:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:13][CH3:14])=[O:12].[CH:43](Br)([CH3:45])[CH3:44]>>[C:11]([CH:15]([N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[CH:43]([CH3:45])[CH3:44])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O:13][CH3:14])=[O:12]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Reactant: CC(C)Br
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(C(C)C)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines with LiN(TMS)2 described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy -1-phenylmethyl)amino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 28) was alkylated with isopropyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([N:19]1[C:31]2[C:30]([S:32]([CH3:34])=[O:33])=[C:29]([CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:28]=[C:27]([CH3:42])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([N:19]1[C:31]2[C:30]([S:32]([CH3:34])(=[O:9])=[O:33])=[C:29]([CH2:35][C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[CH:28]=[C:27]([CH3:42])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(CC(=O)OC(C)C)c(S(C)=O)c2c1c1ccccc1n2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CC(=O)OC(C)C)c(S(C)(=O)=O)c2c1c1ccccc1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
44 mg (0.25 mmol) of m-chloroperbenzoic acid was added to 6 ml of a solution of 100 mg (0.23 mmol) of isopropyl (9-benzyl-1-methylsulfinyl-4-methylcarbazol-2-yl)acetate, as obtained in Example 215 below, in methylene chloride at room temperature, and the mixture was stirred for 30 minutes. After this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, the aqueous layer was extracted with methylene chloride, the extract was dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 50% v/v solution of ethyl acetate in hexane) to yield 90 mg (87%) of the title compound as an amorphous solid.
Reaction SMILES: O[C:2]1([C:8]2[N:9]=[C:10]([CH3:13])[S:11][CH:12]=2)[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1>>[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([N:4]2[CH2:5][CH2:6][O:7][CH:2]([C:8]3[N:9]=[C:10]([CH3:13])[S:11][CH:12]=3)[CH2:3]2)[CH3:26])=[CH:20][CH:19]=1
Reactant: Cc1nc(C2(O)CNCCO2)cs1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Product: Cc1nc(C2CN(C(C)Cc3ccc(OCCO)cc3)CCO2)cs1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)morpholine with 1-[4-(2-hydroxyethyoxy)phenyl]propan-2-one followed by purification on a silica gel column using methylene chloride as eluant.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[N:17]=[CH:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)([O-:29])=[O:28]>CN(C)C=O>[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:14]2[C:15](=[O:21])[C:16]3[N:17]=[CH:18][N:19]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=5)=[CH:10][CH2:11][N:12]([C:20]=34)[C:13]2=[O:22])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=c1[nH]c(=O)n2c3c1ncn3C(c1cccc(C(F)(F)F)c1)=CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn3c2n(c(=O)n1Cc1ccc([N+](=O)[O-])cc1)CC=C3c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a stirred suspension of 5.0 g of 4-[3-(trifluoromethyl)phenyl]-6H,8H-pyrimido[1,2,3-cd]purine-8,10-(9H)-dione (prepared as described in Example 41) in 50 ml of dry N,N-dimethylformamide at room temperature, under nitrogen, was added 800 mg of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 2 hours, then 3.3 g of p-nitrobenzyl bromide in 10 ml of N,N-dimethylformamide was added and the mixture was stirred at room temperature for 40 hours. The mixture was evaporated to dryness, then was treated with water. The solid formed was collected by filtration, washed with water and dried in vacuo. The solid was stirred with 200 ml of dichloromethane and filtered. The filtrate was passed through a short column of magnesium silicate and the eluate was evaporated in vacuo to give 4.34 g of the product of the example which was recrystallized from isopropyl alcohol/acetonitrile as a white solid, mp 230°-232° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>ClCCCl>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)c(O)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To a solution of 2-hydroxy-p-anisic acid (0.2 g, 1.2 mmol) in DCE (8 mL) was added thionyl chloride (0.13 mL, 1.8 mmol) and a drop of DMF. After stirring at room temperature for 4.5 h the reaction mixture was concentrated and azeotroped several times with benzene to give the acid chloride 123 as a white solid (222 mg).
Reaction SMILES: [I-].[C:2]([O:10][CH2:11][Zn+])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]([O:10][CH2:11][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: O=C(OC[Zn+])c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(OCc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
Title compound was prepared according to the procedure described in: Hasnik, Z.; Silhar, P.; Hocek, M. Synlett 2008, 4, 543. A solution of (benzoyloxymethyl)zinc(II) iodide Part B (2.17 mL, 1.949 mmol) was added to a solution of 2-bromo-5-chloropyridine (125 mg, 0.650 mmol) and Pd(PPh3)4 (37.5 mg, 0.032 mmol) in THF (1.30 mL). The reaction mixture was stirred at RT for 5 h at which point it was quenched with 1M NaH2PO4 (30 mL) The solid formed was filtered and washed well with water. The filtrate was extracted with DCM (3×25 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was subjected to flash chromatography (silica gel/hexanes-EtOAc 100:0 to 50:50 gradient) to afford (5-chloropyridin-2-yl)methyl benzoate 16C (101 mg, 63% yield) as an off-white solid. LC-MS, [M+H]+=248. HPLC-Method 8; 3.30 min.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:45]1([OH:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.Br[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60]>>[C:45]1([O:51][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Oc1ccccc1
Reactant: OCCCCCCCBr
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: OCCCCCCCOc1ccccc1

Procedure:
In a further aspect, the invention provides a method of making a bacterial NAD synthetase inhibitor compound comprising the steps of: a. alkylating a phenol with 7-bromo-1-heptanol to provide 7-(phenyloxy)-1-heptanol; b. mesylating 7-(phenyloxy)-1-heptanol to provide 7-(phenyloxy)-1-heptyl methanesulfonate; c. esterifying 7-(phenyloxy)-1-heptyl-methanesulfonate to provide 7-phenyloxy)-1-heptyl nicotinate; and d. n-methylating 7-(phenyloxy)-1-heptyl nicotinate to provide [7-(phenyloxy)-1-heptyl-(N-methyl)nictotinate]iodide.