Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:13]1([S:19]([CH:22]=[C:23](SC)[S:24][CH3:25])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH:22]=[C:23]([S:24][CH3:25])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]2[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSC(=CS(=O)(=O)c1ccccc1)SC
Reactant: NCCSCc1ncccc1Cl
Product: CSC(=CS(=O)(=O)c1ccccc1)NCCSCc1ncccc1Cl

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine-with 1-benzenesulphonyl-2,2-bis-methylthioethylene by the procedure of Example 1(b)(i) yields 1-benzenesulphonyl-2-methylthio-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]ethylene.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][CH:6]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=1.[OH-].[K+].C1COCC1>CO.O>[C:34]1([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@H:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:9]=2)[CH2:5][CH2:4][C:3]([OH:41])=[O:2])=[O:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)CCC(Cc1cn(CCCc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC[C@@H](Cc1cn(CCCc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.67 h
Yield: 75.5 %

Procedure:
To a solution of 4-(7-phenyl-heptanoylamino)-5-[1-(3-phenyl-propyl)-1H-indol-3-yl]-pentanoic acid methyl ester (95 mg, 0.172 mmol) in MeOH (0.5 mL) was added KOH (100 mg, 1.79 mmol) in water (0.5 mL). THF (1 mL) was added to homogenise the solution and the reaction was complete in 40 minutes. The solvents were removed and water added. Upon washing with ether the aqueous layer was acidified with aqueous HCl and the resultant precipitate filtered. Upon drying the solid was recrystallised from THF/Et2O to afford the title compound (70 mg, 76%), mp 100-101.5° C. 1H NMR (DMSO-d6) δ 7.64-7.59 (2H, m), 7.35-7.08 (12H, m), 7.03-6.98 (1H, m), 4.10 (2H, t, J=6.59 Hz), 4.04 (1H, br s), 2.84 (1H, dd, J=6.65, 14.39 Hz), 2.78 (1H, dd, J=6.45, 14.39 Hz), 2.55-2.49 (4H, m), 2.34-2.12 (2H, m), 2.05-2.00 (4H, m), 1.86-1.75 (1H, m), 1.66-1.44 (5H, m), 1.21 (4H, m), 13C NMR (DMSO-d6) □ 174.4, 171.9, 142.3, 141.3, 135.9, 128.3, 128.2, 128.0, 126.5, 125.8, 125.5, 120.9, 118.9, 118.3, 117.9, 110.9, 109.5, 35.6, 35.1, 32.4, 31.5, 30.9, 30.7, 30.5, 29.2, 28.5, 28. 5, 25.3. ISMS: 539 (M+H).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].Cl>O1CCCC1.C(Cl)(Cl)Cl>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:5]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Pro-OH (73.2 g, 340 mmol) and triethylamine (47.6 ml, 340 mmol) in tetrahydrofurane (300 ml), cooled to -10°, was added isobutyl chloroformate (44.5 ml, 340 mmol). After 15 min., a solution of H-Gly-OMe.HCl (42.7 g, 340 mmol) and triethylamine (47.6 ml, 340 mmol) in chloroform (300 ml) was added to the stirring solution. The mixture was stirred at 0° for 1 h and at room temperature for 24 h. The organic solvent was removed under reduced pressure and the residue, dissolved in ethyl acetate, was washed with 10% citric acid solution, 4% sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. The solution was evaporated and the oily residue was crystallized on addition of petroleum ether; yield 71.8 g (84%), m.p. 70°-72° C., Rf1 0.70.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH2:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1O>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][C:15]3[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:14]=3[N:13]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: Nc1cc(Br)ccc1O
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 3-amino-4-methoxybenzoic acid (1.84 g, 11.0 mmol) and 2-amino-4-bromophenol (2.0 g, 11.0 mmol) the subtitle compound was obtained (2.0 g, 55%). 1H NMR (CDCl3) δ 7.85(t, 1H), 7.64(dd, 1H), 7.58(d, 1H), 7.41(d, 1H), 6.90(d, 1H), 3.95(s, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][O:39][C:40]1[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][N:41]=1>CN(C)C=O.O.CC#N>[CH3:38][O:39][C:40]1[C:45]([NH:46][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:44][CH:43]=[CH:42][N:41]=1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Reactant: COc1ncccc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ncccc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 110 mg, 0.33 mmol), EDC (126 mg, 0.66 mmol) and HOBT (101 mg, 0.66 mmol) in dimethylformamide (2 ml) was stirred in air at room temperature for 1 h. 2-Methoxy-pyridin-3-amine (40.8 mg, 0.33 mmol) was then added in one charge. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was diluted with water (25 ml) and then extracted with ethyl acetate (60 ml×3). The organic phases were combined, washed by brine (50 ml×3), dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-HPLC (instrument: Gilson GX-281, Column: Shimadzu 15 μm, 250*20 mm*2, Mobile Phase: A=10 mmol NH4HCO3/water B=CH3CN, Flow rate: 30.0 ml/L method: B=80%-90%, 0.0-7.2 min; B=90%-95%, 7.2-7.5 min; B=95%-95%, 7.5 min-11.5 min, the RT=11.0 min) to yield the title compound as a pink solid. 92 mg.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:22][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([OH:6])=[O:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1ccccc1C(=O)Nc1cccc2ccccc12
Reaction time: 0.02 h
Yield: 96 %

Procedure:
To a 30 mm co-rotating twin screw extruder (Werner & Pfleiderer ZSK type) was added at barrel 1 (of 14) 2370 g (16 mol) per hour phthalic anhydride in the form of crushed pellets, and at barrel 2 molten 1-naphthylamine at a rate of 2234 g (15.62 mol) per hour while maintaining a temperature profile of: zone 1=75°, zone 2=83°, zone 3=95°, zone 4= 75° and zone 5=45° C. At a screw speed of 300 rpm, the residence time was about 60 seconds, resulting in a product containing N-1-naphthylphthalamic acid (4365 g, ca. 96% yield based on 1-naphthylamine).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1)[CH3:29]
Reactant: CNC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN(C)C)C3)c(F)c21

Procedure:
By the use of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and dimethylamine, the reaction is similarly carried out as Example 34 to give 7-[2-(dimethylaminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 185°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 0.5 h

Procedure:
A solution of 8 g (22 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid in 100 ml of toluene was treated with 1 drop of dimethylformamide and 8.6 g (67 mmol) of oxalyl chloride. After the mixture had been stirred for 30 minutes at reflux temperature, it was cooled and concentrated. Yield: quantitative.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3cccc(C(=O)c4ccccc4)c3)c2cc1OC
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 3-hydroxybenzophenone (297 mg) was stirred at 170° C. for 10 minutes, the reaction mixture was then purified by thin layer chromatography on silica gel eluting with hexane/acetone (2/1) to obtain 126 mg of the title compound (yield: 65%).
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[Cl:13])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]=1[N:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[S:28]>>[Cl:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:29]=[C:27]([N:26]([C:18]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[CH2:30][CH2:31][CH3:32])[S:28][C:2]=1[CH3:14]
Reactant: CCCN(C(N)=S)c1cc(C(=O)O)ccc1OC
Reactant: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Yield: 70 %

Procedure:
By following the procedure of EXAMPLE 2 and by using 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one (Compound 1-2) and N-(2-methoxy-5-carboxyphenyl)-N-propylthiourea (Compound 12-1), the expected product is obtained in the form of white crystals; yield=70%; m.p.=109° C.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:5][CH:6]1[CH2:8][CH2:7]1)[C:3]#[N:4].CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:20][C:19](=[O:28])[NH:1][C:2]([C:3]#[N:4])([CH3:9])[CH2:5][CH:6]1[CH2:8][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C#N)(CC1CC1)NC(=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 2-Amino-3-cyclopropyl-2-methyl-propionitrile (Example 66a, 5.01 g, 30.9 mmol) in dry THF (119 mL) was added DIEA (12.1 mL, 67.9 mmol) and benzyl carbonochloridate (CAN 501-53-1, 5.57 mL, 37.1 mmol). The reaction was stirred at 45° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography eluting with a gradient of heptane/ethylacetate to yield the title compound (6.2, 60%) as a colorless oil. MS (ESI, m/z): 259.5 (M+H+).
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxyphosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 g, 1.47 mol) . The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3): δ 1.4 (m, 27H) , 1.8 (m, 1H), 1.9 (m, 2H) 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P-H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[CH:13]1([Mg]Br)[CH2:15][CH2:14]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:13]1([C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=2)([OH:3])[CH3:1])[CH2:15][CH2:14]1
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: Br[Mg]C1CC1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)C2CC2)cc1F

Procedure:
The title compound was prepared starting from 1.50 g (8.92 mmol) of 3-fluoro-4-methoxyacetophenone and 35.7 ml (17.8 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.38 g (74% of theory) of the title compound were obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([C:12]([OH:14])=[O:13])=[C:4]([F:15])[C:3]=1[F:16].[CH3:17][Mg]Cl>C1COCC1>[F:11][C:6]1[C:5]([C:12]([OH:14])=[O:13])=[C:4]([F:15])[C:3]([F:16])=[C:2]([CH3:17])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: C[Mg]Cl
Reactant: O=C(O)c1c(F)c(F)c(F)c(C(=O)O)c1F
Solvent: C1CCOC1
Product: Cc1c(F)c(F)c(C(=O)O)c(F)c1C(=O)O

Procedure:
20 g of tetrafluoroisophthalic acid are initially charged in 250 ml of THF and, at from 20 to 40° C., admixed with 88 ml of a 3 molar methylmagnesium chloride solution. Customary aqueous work-up (see Example 3) gives 20.1 g of 2,4,5-trifluoro-6-methylisophthalic acid. The purity of the product is 85% by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(=O)=O>[Br:31][CH2:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CCNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 3-{3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}propan-1-ol (0.41 g, 0.73 mmol) in methylene chloride (4.7 mL) was added slowly a solution of boron tribromide in methylene chloride (3.6 mL, 3.6 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in dry ice when Na2CO3 (saturated aqueous solution) was added. The mixture was filtered and the solid collected was triturated with EtOAc, followed by washing with EtOAc and water successively to give the desired product as an off-white powder (322 mg, 96%). LCMS for C21H23BrClN4O (M+H)+: m/z=461.0, 463.0. 1H NMR (400 MHz, CD3OD): δ 7.96 (s, 1H), 7.92 (s, 1H), 7.37 (m, 3H), 7.16 (t, J=7.2 Hz, 1H), 6.94 (m, 1H), 6.62 (m, 2H), 3.75 (t, J=7.6 Hz, 2H), 3.43 (t, J=6.8 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.76 (t, J=8.0 Hz, 2H), 2.15 (m, 2H).
Reaction SMILES: [P:1]([O:35]CC1C=CC=CC=1)([O:27]CC1C=CC=CC=1)([O:3][C:4]1[C:9]2[CH2:10][O:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[O:25][CH3:26])=[O:2]>CO.[Pd]>[P:1]([OH:35])([OH:27])([O:3][C:4]1[C:9]2[CH2:10][O:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[O:25][CH3:26])=[O:2]
Reactant: COc1ccc2c(c1OP(=O)(OCc1ccccc1)OCc1ccccc1)COCc1cc(OC)c(OC)c(OC)c1-2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1OP(=O)(O)O)COCc1cc(OC)c(OC)c(OC)c1-2
Yield: 96.3 %

Procedure:
3,9,10,11-Tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-yl bis(phenylmethyl) phosphate (39.4 mg, 0.067 mmol) in methanol (3 mL) was stirred with palladium on charcoal (10% w/w; 4 mg) under hydrogen for 2 hours at room temperature and pressure until TLC indicated the consumption of the starting material. The mixture was then passed through a small silica plug (0.5 cm depth in a Pasteur pipette) and concentrated to afford 3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-yl dihydrogen phosphate as a white crystalline solid (26.6 mg, 97%); m.p. 132° C.; High Resolution Mass Spectrometry Found: M+Na+ 435.0826 (C18H21O9PNa requires 435.0821); νmax/cm−1 (thin film) 2930, 2858, 1590, 1107; NMR Spectrum δH (400 MHz, CD3OD) 3.56 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.82-3.87 (1H, m, 5-H or 7-H), 3.90-3.95 (1H, m, 5-H or 7-H), 4.34 (1H, apparent d, J 9.6 Hz, 5-H or 7-H), 5.12 (1H, apparent d, J 9.6 Hz, 5-H or 7-H), 6.86 (1H, s, 8-H), 7.12 (1H, d, J 8.7 Hz, 2-H), 7.42 (1H, br d, J 8.7 Hz, 1-H); NMR Spectrum δC (100 MHz, CD3OD) 56.94, 57.01, 61.43, 61.72, 61.86, 68.82, 101.28, 110.55, 113.71, 127.80, 128.05, 129.71, 131.78, 132.69, 144.52, 152.19, 154.90; NMR Spectrum δP (160 MHz, CD3OD)-3.52 (P); m/z (ES) 435 (MNa+, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.[Na].F[B-](F)(F)F.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH2:38])=[NH:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([C:36]2[N:38]=[C:7]([OH:9])[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:11]([OH:13])[N:37]=2)[CH:39]=[CH:40][CH:41]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: N=C(N)c1cccc(OCc2ccccc2)c1
Agent: F[B-](F)(F)F
Agent: [Na]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(-c2cccc(OCc3ccccc3)c2)nc1O
Reaction time: 0.5 h

Procedure:
6.3 g of dimethyl (2-methoxyphenoxy)malonate were added dropwise within 5 minutes under an argon atmosphere to a solution of 1.72 g of sodium in methanol (150 ml) at 5° C. Stirring was continued for 30 minutes (5° C.) then 7.85 g of m-benzyloxy-benzamidine tetrafluoroborate in methanol (50 ml) were added within 5 minutes at 5° C. and the mixture was then stirred for further 20 h at RT. The solvent was removed in vacuo and the residue partitioned between water and EtOAc (each 50 ml). The cold aqueous phase was acidified dropwise with conc. HCl the precipitate filtered off under suction, washed with water and dried under reduced pressure to give the desired 2-(3-benzyloxy-phenyl)-5-(2-methoxy-phenoxy)-pyrimidine-4,6-diol as an off-white solid, mp 192°-195° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=2)[C:31](O)=[O:32])[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:28]2[CH:29]=[C:30]([C:31]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:17]([CH2:16][O:15][C:14]4[C:4]5[C:3]([NH2:2])=[N:8][S:7](=[O:9])(=[O:10])[NH:6][C:5]=5[CH:11]=[CH:12][CH:13]=4)[CH2:18]3)=[O:32])[CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)c4ccnc(-n5ccnc5)c4)C3)c21

Procedure:
Prepared as in Example 2 from (S)-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide hydrochloride (Example 2a) and 2-(1H-imidazol-1-yl)isonicotinic acid (Example 52a) (42% yield). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ1.42-1.60 (m, 2H), 1.71 (m, 1H), 1.93 (m, 1H), 2.22 (m, 1H), 3.11 (m, 1H), 3.34-3.75 (m, 1H), 3.92-4.42 (m, 2H), 6.63 (m, 1H), 6.74 (br s, 1H), 7.11 (s, 1H), 7.29 (m, 1H), 7.42 (m, 1H), 7.52-8.28 (br s, 2H), 7.76 (m, 1H), 7.93 (m, 1H), 8.52 (m, 2H), 10.71 (br s, 1H). MS 482 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=O)[CH3:5])[CH3:2].[P:7]([OH:10])([OH:9])[OH:8].Cl>>[CH2:1]([NH:3][C:4]([P:7]([OH:10])(=[O:8])[OH:9])([P:7]([OH:10])(=[O:9])[OH:8])[CH3:5])[CH3:2]
Reactant: CCNC(C)=O
Reactant: OP(O)O
Agent: Cl
Product: CCNC(C)(P(=O)(O)O)P(=O)(O)O

Procedure:
Into a mixture of 87 gm of N-ethylacetamide and 82 gm of phosphorous acid, hydrogen chloride was introduced for 8 hours. During this time the mixture was stirred and the temperature was held at 150° - 160° C. The reaction mixture was then treated analogously to Example 1, and the N-ethyl-1-aminoethane- 1,1 -diphosphonic acid product was obtained. The yield was 36.5 gm.
Reaction SMILES: [CH2:1]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1.[NH4+].[Cl-].C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[CH2:31][N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCCCCCCNS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
N--Octyl-toluene-4-sulfonamide (7.0 g, 0.025 mol) was dissolved in dry THF (200 ml) and cooled to -78° C. A 1M solution of LHMDS in THF (27.2 ml, 0.028 mol) was then added over 10 minutes. The reaction mixture was allowed to warm to -400° C. with stirring over 30 minutes. Neat tert-butyl bromoacetate (4.8 ml, 0.03 mol) was added over 5 minutes and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl (200 ml) and ethyl acetate (200 ml). The organic layer was separated and washed consecutively with 1M HCl, 0.5M Na2CO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (silica gel, 6% ethyl acetate in hexane) to give the title compound as a white solid (5.2 g, 53%). 1H NMR: δ (CDCl3), 7.72 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.4 Hz), 3.94 (2H, s), 3.23 (2H, dd, J=7.5, 7.6 Hz), 2.42 (3H, s), 1.60-1.42 (2H, m), 1.39 (9H, s), 1.34 -1.17 (10H, m), 0.88 (3H, t, J=6.9 Hz).