Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:34](=[O:35])[CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:37])([F:38])[F:24])=[CH:31][CH:30]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)CCc1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(C(F)(F)F)cc1)c1cccc(OC(F)(F)F)c1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
To a solution of 522 mg (2.5 mmol) 3-(trifluoromethoxy)phenylboronic acid in 10 ml toluene under argon at RT, was added successively 29.7 mg (0.04 mmol) Pd(PPh3)2Cl, 776.5 mg (3.2 mmol) K3PO4.H2O and 500 mg (2.1 mmol) 3-(4-Trifluoromethyl-phenyl)-propionyl chloride (CAS: 539855-79-3). The reaction mixture was heated at 110° C. for 3 h, cooled to RT and ethyl acetate was added. The solution was washed successively with NaHCO3 sat., water and brine. The organic phase was dried over Na2SO4 and evaporated. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.44 g (58%) of the title compound as colorless oil. MS (m/e): 363.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: NCCO
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCCO)nc1
Yield: 96 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (110 mg, 96%), which was obtained as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [CH3:1]/[C:2](/[O-])=[CH:3]/[C:4]([CH3:6])=O.[CH3:8]/[C:9](/[O-])=[CH:10]/[C:11]([CH3:13])=O.[Ni+2:15].[O-]CC.C([Al+]CC)C>CCCCCC.C1CCC=CCCC=1>[Ni:15].[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:1][CH:2]=[CH:3][CH:4]=1.[CH:13]1[CH2:3][CH2:2][CH2:1][CH2:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)/C=C(/C)[O-]
Reactant: [Ni+2]
Agent: CC[Al+]CC
Agent: CC[O-]
Solvent: C1=CCCC=CCC1
Solvent: CCCCCC
Product: C1=CCCCCC=C1
Product: [Ni]

Procedure:
20 m moles of nickel acetylacetonate was suspended in 20 ml of n-hexane and 20 ml of 1,5-cyclooctadiene, and an n-hexane solution containing 100 m moles of diethyl aluminum ethoxide [(C2H5)2AlOC2H5 ] was added dropwise thereto at a temperature of -5° to -10° C. The resulting yellow colored crystals were filtered out and then recrystallized from benzene. Thus, bis-cyclooctadiene nickel was obtained.
Reaction SMILES: C(OC[C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.O.[C:32]([O-:35])(=[O:34])[CH3:33].[Na+:36].[CH3:37]O>>[C:32]([O:35][C:37]1[CH:7]([CH3:6])[S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:34])[CH3:33].[Na+:36]
Reactant: CC(=O)[O-]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: CO
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(OC(C)=O)C(C)S[C@H]12)c1csc(N)n1
Yield: 4 %

Procedure:
108.7 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid containing 8% ethanol and 0.5% water were added at 0° to 2° C. under a nitrogen atmosphere to a stirred solution of 21.6 g of anhydrous sodium acetate, 25 ml of dimineralized water and 175 ml of anhydrous pure methanol and the resulting solution was stirred at 0° to 2° C. under nitrogen and was then passed through a heat insulated sterile filter. The filtrate was recovered at 0° to 2° C. under nitrogen in a sterile container and the filter was rinsed twice with 25 ml of anhydrous pure methanol. The sterile solution held at 0° to 2° C. under nitrogen under went normal precipitation over one hour with stirring under nitrogen in 500 ml of ethanol containing 2% of water at 18°-20° C. The resulting suspension was held with stirring under nitrogen for several hours and was then vacuum filtered. The recovered product was empasted successively with 100 ml and then 200 ml of ethanol containing 5% water and was then washed with 50 ml of ethanol containing 5% of water to obtain a damp product which was dried under reduced pressure at 20°-25° C. to obtain 96.5 g of the cystalline D form of the syn isomer of sodium 3-acetoxy-methyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate containing 4% of water and ≃0.4% of ethanol. The infrared spectrum showed it was the D form.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][C:16](=[O:27])[CH:17]([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:27])[CH:17]([CH3:26])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2][C:3]2[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: CC(C)Sc1ncccc1CCl
Product: CCOC(=O)C(C)Cc1ccc(OCc2cccnc2SC(C)C)cc1
Yield: 53.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.063 g, 0.31 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.065 g, 0.31 mmol) obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.062 g, 53%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13]>>[Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH2:8][O:13][CH2:12][C:11]([F:15])([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(F)n1
Reactant: OCC(F)(F)F
Product: Fc1nc(COCC(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in an analogous manner to that described in Example 198 (Step 1) using 3-bromo-2-fluoro-6-methylpyridine (1.44 g, 7.58 mmol) (Waterstone Technology) and 2,2,2-trifluoroethanol. 1H NMR (400 MHz, d6-DMSO) δ 8.34 (1H, t, J=8.5 Hz); 7.34 (1H, d, J=7.9 Hz); 4.69 (2H, s); 4.22 (2H, q, J=9.5 Hz). m/z (ESI, +ve ion) 288/290 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1.CCOCC>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5-hexynyl alcohol (102 mmoles) in pyridine (150 ml), under argon, was cooled to 0° C. and p-toluenesulfonyl chloride (204 mmoles) was added. The reaction mixture was kept at about 4° C. for 18 hours, poured into ice-water and then taken up in ether. The ether extract was washed with cold 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated in vacuo to give 5-hexynyl p-toluenesulfonate. A solution of phenylacetylene (97 mmoles) in tetrahydrofuran (200 ml) containing a trace of triphenylmethane was cooled to 0° C. and then n-butyl lithium (37.3 ml of 2.6 moles in hexane) was added dropwise. The resulting solution was stirred at 0° C. for 10 minutes and hexamethylphosphoramide (21 ml) was added dropwise. After stirring for 10 minutes a solution of 5-hexynyl p-toluenesulfonate (97.1 mmoles) in tetrahydrofuran (200 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with ether and the organic layer was washed with water and brine. The dried organic solution was concentrated and the product was purified by flash chromatography to give 1-phenylocta-1,7-diyne. A mixture of this compound (43 mmoles), 2-bromobenzaldehyde (35.8 mmoles), cuprous iodide (0.5 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.7 mmoles) in triethylamine (100 ml) was heated in an oil bath (95° C.) for one hour. The reaction mixture was cooled to 0° C., filtered and the filtrate was concentrated. The residue was dissolved in ether, washed with 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated to give a product which was purified by flash chromatography to yield 2-(8-phenyl-1,7-octadiynyl)benzaldehyde. A solution of this compound (24.1 mmoles) in ethyl acetate (100 ml) and 10% palladium on charcoal (1 g) was hydrogenated (40 psi of hydrogen) at room temperature for 15 minutes. The catalyst was filtered off and the filtrate concentrated to give the 2-(8-phenyloctyl)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>ClCCl>[NH3:6].[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:35])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N
Product: O=C(N1CCOCC1)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 125.3 %

Procedure:
A mixture of the amine from example 4 (150 mg, 0.42 mmol), morpholinecarbonyl chloride (0.15 ml, 1.26 mmol) and triethylamine (0.18 ml, 1.26 mmol) in dichloromethane (10 ml) was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5), to afford the title compound as a white solid (130 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[C:26](Cl)(Cl)=[S:27]>C(Cl)(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:16]=[C:26]=[S:27])=[CH:17][CH:18]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(N)cc2)nc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCc1ccc(-c2ccc(N=C=S)cc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1.256 g of p-(5-pentyl-2-pyridyl)aniline in 29 ml of chloroform was treated at 5° C. under nitrogen with 1.46 ml of triethylamine. Then, at 1° C. within 20 minutes a solution of 0.49 ml of 95 percent thiophosgene in 14.5 ml of chloroform was added dropwise to the reaction mixture so that the temperature did not exceed 3° C. The reaction mixture was subsequently stirred at room temperature for 45 minutes and under reflux for a further 40 minutes, then cooled and washed with 40 ml of 3N ammonia and with water. The aqueous phases were back-extracted with methylene chloride. The organic phases were dried over sodium sulphate, filtered and freed from solvent. Purification of the resulting brownish paste (1.56 g) by chromatography on 60 g of silica gel with 700ml of methylene chloride/hexane (vol. 1:1) and subsequent crystallization from diethyl ether/hexane gave 1.17 g of p-(5-pentyl-2-pyridyl)phenylisothiocyanate as colourless crystals with m.p. (C--SA) 36.3° C. and cl.p. (SA --I) 97.2° C.
Reaction SMILES: [Na].[C:2]([OH:10])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:13][CH:14]([O:18][CH2:19][CH3:20])[CH2:15][CH2:16]Cl)[CH3:12].O>CN(C)C=O>[C:2]([O:10][CH2:16][CH2:15][CH:14]([O:18][CH2:19][CH3:20])[O:13][CH2:11][CH3:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(CCCl)OCC
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCOC(=O)c1ccccc1)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 50.0 grams (0.347 mole) of the sodium salt of benzoic acid and 53.0 grams (0.320 mole) of 3-ethoxy-4-oxahexyl chloride in 500 ml of dimethylformamide was heated at reflux for three hours. The reaction mixture was cooled to ambient temperature, and 500 ml of water was added. The mixture was extracted with two 700 ml portions of diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 57.5 grams of 3-ethoxy-4-oxahexyl benzoate. The nmr spectrum was consistent with the proposed structure. Further extraction of the aqueous layer with diethyl ether yielded an additional 34.7 grams of the benzoate.
Reaction SMILES: Cl.[NH2:2]C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC)=CC=3)=C(C#N)C=NN2C=1.C(NC1C=CC(C(O)=O)=CC=1)(=O)C.[C:44]([NH:47][C:48]1[CH:49]=[C:50]([CH:82]=[CH:83][CH:84]=1)[C:51]([NH:53][C:54]1[C:55]([CH3:81])=[C:56]2[C:61]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=4[O:76][CH3:77])=[CH:65]C=3)=[C:60]([C:78]#[N:79])[CH:59]=[N:58][N:57]2[CH:80]=1)=[O:52])(=[O:46])[CH3:45]>>[C:44]([NH:47][C:48]1[CH:49]=[C:50]([CH:82]=[CH:83][CH:84]=1)[C:51]([NH:53][C:54]1[C:55]([CH3:81])=[C:56]2[C:61]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=4[O:76][CH3:77])=[CH:65][N:2]=3)=[C:60]([C:78]#[N:79])[CH:59]=[N:58][N:57]2[CH:80]=1)=[O:52])(=[O:46])[CH3:45]
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)c4cccc(NC(C)=O)c4)c(C)c23)cc1
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N)c(C)c23)cc1
Agent: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)c4cccc(NC(C)=O)c4)c(C)c23)nc1
Yield: 50 %

Procedure:
The title compound (27.3 mg, 50%) was prepared from the hydrochloride salt of 430F (42 mg, 0.10 mmol) and 4-acetylamino-benzoic acid (27 mg, 0.15 mmol) by a route analogous to that used for the preparation of compound 430. It is a slight yellow solid and has a retention time of 6.14 min (standard LC1 method, 8 min run). MS Found: (M+H)+=547.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:35]([OH:37])=O)[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].[CH3:38][NH:39][CH3:40]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:35]([N:39]([CH3:40])[CH3:38])=[O:37])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: CNC
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(=O)O)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(=O)N(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from (S)-4-((1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylic acid (0.549 mmol, 300 mg) and N,N-dimethylamine (0.824 mmol, 37 mg). The product was purified by flash-chromatography. Yield 207 mg. 1H-NMR (400 MHz; CDCl3): δ −0.01 (s, 9H), 0.91 (t, 2H), 1.26 (d, 3H), 3.11 (s, 3H), 3.26 (s, 3H), 3.54 (t, 2H), 4.31-4.42 (m, 2H), 4.51-4.57 (m, 1H), 5.74 (s, 2H), 6.59 (d, 1H), 7.39 (d, 1H), 7.49 (d, 1H), 7.59 (d, 1H), 7.81 (s, 1H), 7.84 (s, 1H). LC-MS: [M+1]=574.32.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[CH2:9]([O:16][CH:17]([C:22](=O)[C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>CO>[CH2:9]([O:16][C:17]1[C:18](=[O:19])[N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2=[N:2][C:22]=1[C:23]([O:25][CH3:26])=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)C(OCc1ccccc1)C(=O)OC
Reactant: N=C1CCCCN1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCC2
Reaction time: 48 h

Procedure:
Commercially available 2-iminopiperidine hydrochloride (1.5 eq) was added at room temperature to a solution of oxosuccinate prepared in Step 1b (1 eq) in MeOH. After dropwise addition of neat DBU (4.5 eq), the reaction mixture was stirred for 2 days. Evaporation of the solvent gave a residue that was taken into EtOAc and washed with 1N HCl and brine; the organic layer was dried on Na2SO4 and the solvent removed. The crude was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:22][O:23][CH2:24][CH3:25])([OH:21])[CH:6]([N+:18]([O-])=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[H][H]>[Ni].C(O)(C)C>[CH2:24]([O:23][CH2:22][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:21])[CH:6]([NH2:18])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:25]
Reactant: [H][H]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: CCOCC(O)(COCC)C(N)Cc1cccc2ccccc12
Yield: 90 %

Procedure:
A mixture of α, α-diethoxymethyl-β-nitro-1-naphthalenepropanol (7.75 g) and Raney nickel (0.8 g) in isopropanol (100 ml) was stirred under hydrogen at atmospheric pressure until hydrogen absorption stopped. The mixture was then degased for 15 minutes in vacuo and filtered through celite. The filtrate was evaporated in vacuo to yield α, α-diethoxymethyl-β-amino-1-naphthalenepropanol (6.37 g) as an oil.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][P:14]([CH3:18])(=[O:17])[O:15][CH3:16].[CH2:19]([P:30](Cl)(=[O:34])[O:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:13][P:14]([CH2:18][P:30]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])([O:31][CH2:32][CH3:33])=[O:34])(=[O:17])[O:15][CH3:16]
Reactant: C=CCCCCCCCCCP(=O)(Cl)OCC
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCCCCCCP(=O)(CP(=O)(OC)OC)OCC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A 2.5 M solution of n-butyllithium in hexane (9.4 mL, 23.5 mmol) was added dropwise with stirring to methylphosphonic acid dimethyl ester (2.65 g, 21.4 mmol) in 100 mL of anhydrous tetrahydrofuran at −78° C. under a nitrogen atmosphere. After 30 minutes, (10-undecenyl)phosphono chloridic acid, ethyl ester (3 g, 10.68 mmol) was added dropwise while stirring was continued. The reaction was stirred at −78° C. for 2 hours then warmed to −50° C. and stirred for an additional 2 hours. Saturated ammonium chloride was then added to neutralize the excess base and the reaction was allowed to warm to ambient temperature. The volatiles were removed by rotary evaporation to give a viscous liquid. This liquid was diluted with ethyl acetate (200 mL) and extracted twice with water (100 mL). The organic layer was collected and dried over sodium sulfate, filtered and concentrated under rotary evaporation to give a viscous liquid. The product was then placed on a high vacuum pump to remove any remaining volatiles (3.07 g, 78% yield).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].CS(O[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[S:22][C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[C:25](=[O:27])[N:26]=2)[N:16]=1)(=O)=O.[C:32](OCC)(=O)C>CN(C=O)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:32][C:15]1[N:16]=[C:17]([C:21]2[S:22][C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[C:25](=[O:27])[N:26]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(CSc3ccccn3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
2-mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil, 0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.60 g, 1.72 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.54 g, 87%) as pale yellow crystals.
Reaction SMILES: [C:1]([N:4]([C:6]1[N:11]=[C:10]([C:12]([O:14]C)=[O:13])[C:9]([O:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)=[CH:8][CH:7]=1)C)(=O)C.[OH-].[K+].O>CO>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([O:25][CH3:26])[N:18]=[C:17]([O:16][C:9]2[C:10]([C:12]([OH:14])=[O:13])=[N:11][C:6]([NH:4][CH3:1])=[CH:7][CH:8]=2)[N:22]=1
Reactant: COC(=O)c1nc(N(C)C(C)=O)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1ccc(Oc2nc(OC)cc(OC)n2)c(C(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
195.6 g (0.54 mol) of methyl 6-(N-acetyl-N-methylamino)-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate was dissolved in 1.5 l of methanol. The solution was added to 335 g of a 20% potassium hydroxide aqueous solution, and the mixture was stirred for one hour at 50° C. The reaction solution was concentrated, and 1 l of ice water was added thereto. The mixture was acidified (to about pH4) with an aqueous citric acid solution and left to cool. Precipitated crystals were collected by filtration and washed with cool water and diisopropyl ether. Then, the crystals were dissolved in 1 l of methanol, and 45.6 g (0.69 mol) of potassium hydroxide and 50 ml of water were added thereto. The mixture was stirred at room temperature for 28 hours. The reaction solution was concentrated, and ice water was added thereto. The mixture was acidified with an aqueous citric acid solution to obtain crude crystals. The crystals were washed with diisopropyl ether and then dried under reduced pressure at 90° C. for 24 hours to obtain 112 g (yield: 68%) of the desired product as a white powder.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([N:19]=[C:20]=[S:21])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[NH3:22]>C1COCC1>[Si:5]([O:8][CH:9]1[CH2:10][C:11]2[C:12]([NH:19][C:20]([NH2:22])=[S:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N=C=S)c2C1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(NC(N)=S)c2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the product of Example 18C (1.25 g, 3.91 mmol) in THF (50 mL) was treated with 7N methanolic NH3 (5.6 mL, 39.1 mmol), and the mixture was stirred at room temperature for 6 hours. The mixture was partitioned between EtOAc and H2O, and the separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. Silica gel chromatography (98:2 to 95:5 CH2Cl2:CH3OH eluant) provided the title compound as a pale yellow solid, 1.27 g (97%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.6-7.8 (br, 2H), 6.99-7.13 (m, 3H), 4.08 (m, 1H), 2.73-2.92 (m, 4H), 1.84-1.92 (m, 1H), 1.60-1.68 (m, 1H). MS (ESI+) m/z 337 (M+H).