Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)C(C)C)(C)C.[C:20]([O:24][C:25](=[O:33])[NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25](=[O:33])[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:29][CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution of 1-fluoro-2-nitro-benzene (0.50 mmol, 53 μL), N,N-diisopropylethylamine (0.50 mmol, 87 μL) and Piperidin-4-yl-carbamic acid tert-butyl ester (0.50 mmol, 0.10 g) in 1,4-dioxane (2 mL) was irradiated using microwave for 10 minutes at a temperature of 180° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide [1-(2-Nitro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.12 g, 77% yield). To the solution of this nitro compound in EtOAc (15 mL) was added Pd on carbon (5% Pd, 55 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide Intermediate Compound 42A (97 mg, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:15])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)nc(N)n1
Product: CC(C)(C)c1cc(Cl)nc(N)n1

Procedure:
2-Amino-4-hydroxy-6-tert-butylpyrimidine (8.35 g) was dissolved in 50 mL of phosphorus oxychloride and the solution refluxed for 2 hours. Excess phosphorus oxychloride was removed under vacuum and the residue dissolved in 100 mL of ethanol. The solution was adjusted to pH 8 with ice-cold concentrated ammonium hydroxide, and solvent removed under reduced pressure. The residue was filtered to give a white solid, which was recrystallized from ethanol-water to give 2-amino-4-chloro-6-tert-butylpyrimidine (3.66 g), m.p. 87.7-88.9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:9][C:10](=O)[NH:11][C:12]=2[N:13]=1)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:9][CH:10]=[N:11][C:12]=2[N:13]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])nc2N1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(n1)N=CCO2

Procedure:
6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (500 mg) was refluxed with boron hydride methyl sulfide complex (1 mL) in THF (10 mL) for 30 min to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazine. In a manner analogous to the preparation of 5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine, 6-nitro-2H-pyrido[3,2-b]-1,4-oxazine was reduced and reacted with 2,4-dichloro-5-fluoropyrimidine (500 mg) and 3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give 5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamine as a gray solid. 1H NMR (CD3OD): δ 2.81 (s, 3H), 3.48 (t, J=4.5 Hz, 2H), 4.14 (t, J=4.5 Hz, 2H), 4.44 (s, 2H), 6.60 (ddd, J=1.5 and 2.7 and 7.5 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.42 (t, J=2.1 Hz, 1H), 7.92 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −168.20; LCMS: ret. time: 25.49 min.; purity: 97.56%; MS (m/e): 426.23 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]2[O:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:3]1=[O:23].[H][H]>[Pd].C(O)C>[NH:15]=[C:16]([C:4]1[C:3](=[O:23])[N:2]([CH3:1])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]=1[OH:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: Cn1c(-c2ccccn2)cc2onc(-c3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CCO
Product: Cn1c(-c2ccccn2)cc(O)c(C(=N)c2ccccc2)c1=O

Procedure:
A mixture of 16.5 g. (0.0545 mole) of 5-methyl-3-phenyl-6-(2-pyridyl)-isoxazolo[4,5-c]pyridin-4(5H)-one, 330 ml. ethanol and 1.65 g. 10% palladium on carbon is hydrogenated at 50 psi and room temperature. The hydrogenation is ceased after one equivalent of hydrogen is absorbed (ca. 2.5 hours). The mixture is treated with methylene chloride and the catalyst is removed by filtration. The solvents are removed in vacuo to a volume of ca. 50 ml. and then ether is added, to precipitate solids which are removed by filtration to give 3-(α-iminobenzyl)-4-hydroxy-6-(2-pyridyl)-1-methyl-2(1H)-pyridone; m.p. 242° to 245° C. In order to obtain the sodium salt of the aforementioned compound, for example, the compound is dissolved in methanol and treated with sodium hydroxide solution to yield after evaporation the sodium salt.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:13][P:14](Cl)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.O>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][P:14]([CH3:13])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CP(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
The methylphenylphosphinic acid 4-nitrophenyl ester is prepared in the following way: A suspension of 173 mg of NaH at 50% in oil, in 2 ml of anhydrous tetrahydrofuran, is stirred at ambient temperature under argon. A solution of 500 mg of 4-nitrophenol in 2 ml of anhydrous tetrahydrofuran is added dropwise at ambient temperature. After stirring for approximately 1 hour at ambient temperature, a solution of 630 mg of methylphenylphosphinic chloride in 2 ml of anhydrous tetrahydrofuran is added dropwise over about ten minutes. After stirring for approximately 2 hours, the reaction medium is diluted with 20 ml of distilled water and the aqueous phase is extracted with 2×20 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated under reduced pressure in a rotary evaporator. 995 mg of methylphenylphosphinic acid 4-nitrophenyl ester are obtained with a purity of 50%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:18][O:19][B:20](OC)[O:21][CH3:22]>O1CCCC1>[CH3:18][O:19][B:20]([O:21][CH3:22])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COB(OC)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1-bromo-4-fluoronaphthalene (0.5 g) in 10 mL of tetrahydrofuran at -78° C. under nitrogen was added n-butyllithium (1.6M, 1.53 mL) dropwise. The solution was allowed to stir for 5 minutes, then trimethoxyborane (0.33 mL) was added dropwise. The solution was allowed to warm to room temperature and the solvent removed under reduced pressure to give a solid, dimethoxy-(4-fluoronaphth-1-yl)borane, a compound of formula (7).
Reaction SMILES: CCCCCCCCCCCCCCCCCC(N[C@H]([C@H](O)/C=C/CCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@@:68]3(C(O)=O)[O:73][C@@H:72]([C@H:74](O)[C@H:75](O)[CH2:76]O)[C@H:71](NC(C)=O)[C@@H:70]([OH:84])[CH2:69]3)[C@H]2O)[C@H](O)[C@H]1O)=O.[CH2:108]([OH:110])[CH3:109]>>[CH3:76][C:75]1[C:74]2[CH:72]=[CH:71][C:70]([OH:84])=[CH:69][C:68]=2[O:73][C:108](=[O:110])[CH:109]=1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Reactant: CCO
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
The saliva of each experimental group of Test Example 1 in the present specification was used to examine inhibitory activity against cholera toxin binding. 200 μl of an ethanol solution containing 0.1% ganglioside GM1 (w/v) was added to a 96-well plate for ELISA test. Then, the ganglioside GM1 was adsorbed thereonto by air-drying. The saliva of each experimental group was diluted 10 times with PBS containing 1% bovine serum albumin (BSA) and then reacted for 1 hour by the addition of a biotin-conjugated cholera toxin. 100 μl of the reaction solution was added to the plate for ELISA test, and the plate was left for 30 minutes. Then, the supernatant was removed. The plate for ELISA test was washed several times with PBS containing 0.05% Tween 20. Biotin-binding β-galactosidase was added thereto. The plate for ELISA test was left for a given length of time. Then, the supernatant was removed. The plate for ELISA test was washed several times again with PBS containing 0.05% Tween 20, and the contents in the plate were reacted for 30 minutes by the addition of 4-methylumbelliferyl galactose. Then, 4-methylumbelliferone produced was measured with a fluorophotometer (excitation wavelength: 360 nm, measurement wavelength: 460 nm). Then, an inhibition rate was calculated according to the following formula: Inhibition rate(%)={1−(A/B)}×100, wherein
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.C1C[O:24]CC1>>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([CH2:1][OH:24])[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of 8-methyene-1,4-dioxa-spiro[4.5]decane (2.0 g, 13 mmol, 1.0 eq.) in THF (10 mL) at 0° C. was added dropwise 9-BBN (0.5 M in THF, 104 mL, 4.0 eq.) and the resulting mixture was stirred for 15 min and then warmed to room temperature and stirred overnight. Then NaBO4. 4H2O (32 g, 16 eq.) was introduced at 0° C. portionwise and the resulting mixture was warmed to room temperature and stirred overnight, diluted with hexanes (30 mL) and the separated aqueous phase was extracted with EtOAc. The combined organic phase was dried over over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc-hexanes) to give (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.5 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[S:25][C:24]([C:26]#[N:27])=[CH:23][C:22]=1[CH3:28]>>[CH3:28][C:22]1[CH:23]=[C:24]([C:26]#[N:27])[S:25][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(c1cccs1)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo4-methylthiophene-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.26 (s, 1H), 7.83 (s, 1H), 7.56 (dd, J=4.9, 1.1 Hz, 1H), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 4.23 (d, J=15.9 Hz, 1H), 4.13 (d, J=15.9 Hz, 1H), 2.19 (s, 3H), 2.03 (s, 3H); MS (ES) m/z 381 (M+H)+; Anal. Calc. For C20H16N2O2S2: C, 63.14; H, 4.24; N, 7.36. Found: C, 62.85; H, 4.16; N, 7.09.
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][C:5]1[C:10]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:8]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:7]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:6]=1)[CH3:2].B(F)(F)F.CCOCC.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO>[CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][C:5]1[CH:6]=[C:7]2[C:24]3[CH:28]=[CH:27][S:26][C:25]=3[C:20]3[S:21][CH:22]=[CH:23][C:19]=3[C:8]2=[CH:9][C:10]=1[CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCCCC(CC)Cc1cc(-c2ccsc2)c(-c2ccsc2)cc1CC(CC)CCCC
Agent: FB(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: CO
Product: CCCCC(CC)Cc1cc2c(cc1CC(CC)CCCC)c1ccsc1c1sccc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A dry 500 mL 3-neck flask, flushed with dry nitrogen, was charged with 5 g (10.7 mmol) of 3,3′-(4,5-bis(2-ethylhexyl)-1,2-phenylene)dithiophene. The flask was evacuated and backfilled with nitrogen 3 times. Dry CH2Cl2 (214 mL, 0.05 M) was added to the flask via cannula. The solution was bubbled with nitrogen for 15 min. The solution was then cooled to 5° C. and BF3.Et2O (1.61 mL, 12.9 mmol) was added. DDQ (2.43 g, 10.7 mmol) was added in 0.5 g increments over 30 min. The reaction was monitored by TLC using C18 silica plates in methanol. After DDQ addition was completed, continued to monitor the reaction. At 15 min after DDQ addition, added another 0.1 g of DDQ followed by another 0.1 g addition at 18 min after first DDQ addition. At 30 min after initial DDQ addition, 0.3 mL of BF3.Et2O was added followed by another 1 mL of BF3.Et2O at 40 min. At 1 h after initial DDQ addition was complete, no starting material was noticed by TLC and the reaction was quenched by the adding 3 g of Zn powder followed by stirring of the reaction for 2 h. The mixture was diluted with 200 mL of methanol and stirred for another hour. The mixture was diluted with water and extracted with chloroform (3×500 mL). The organic fractions were dried over MgSO4 and then concentrated. The product was purified by column chromatography using hexane as the eluent to yield the product as pale yellow oil that crystallized upon standing (3.2 g, 64%). 1H NMR (300 MHz, CDCl3): δH 7.90 (d, 2H), 7.37 (d, 2H), 2.77 (m, 4H), 1.72 (m, 16H), 0.89 (m, 12H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH:11]2[N+:15]([O-:17])=[O:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.C1COCC1.O>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[N+:15]([O-:17])=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C1C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a solution of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane-2,4-dione (3.0 g, 12.2 mmol) in dry THF (30 ml) was added NaBH4 (1.15 g, 30.48 mmol). The reaction was stirred for 15 min at r.t. under N2. BF3.THF complex (3.15 ml, 13.4 mmol) was added dropwise and the reaction heated at 40° C. for 4 h. Further NaBH4 (0.15 g) was added followed by BF3.THF complex (0.32 ml). Heating was continued at 45° C. for 30 min. A mixture of THF/H2O (1/1, 60 ml) was added dropwise with stirring. The resulting mixture was heated at 50° C. for 1 h before standing at r.t. for 16 h. The THF was removed to leave mainly water. This was extracted with EtOAc, dried (MgSO4) and evaporated to dryness to give the title compound as a yellow oil (2.47 g, 93%). m/z 219 [M+H]+, 1H NMR (300 MHz, CDCl3) δ: 2.50 (4H, s), 3.15 (2H, d), 3.65 (1H, s), 4.55 (1H, s), 7.2-7.4 (5H, m).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[N:16]=[CH:15]1>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][C:22]3[NH:14][CH:15]=[N:16][C:17]=3[CH2:18]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCCC1CCCCC1
Reactant: c1nc2c([nH]1)CCNC2
Solvent: ClCCl
Product: O=C(CCCCC1CCCCC1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyclohexylpentanoic acid (0.94 g, 5.10 mmol) in DCM (4 mL) carbonyldiimidazole (0.83 g, 5.12 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then added to a solution of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (5.10 mmol) in DCM (4 mL). After 2.5 h DCM (50 mL) was added and the mixture was washed with water (3×15 mL). The organic layer was then dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) whereby 0.35 g (24%) of the title amide was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:15]>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:20]2[CH:19]=[CH:18][S:17][C:16]=2[C:14]([O:13][CH3:12])=[O:15])(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C

Procedure:
To 1.5 g of 2-amino-4,6-dimethoxypyrimidine in 30 ml of anhydrous acetonitrile was added 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonyl isocyanate with stirring at ambient temperature. All of the solid reactant dissolved and after twenty minutes of stirring a precipitate started to form. After two hours the mixture was filtered and the solid which was washed with anhydrous ethyl ether, melted at 191°-193°. The solid showed peaks by nuclear magnetic resonance spectroscopy at 4.0 ppm and 3.8 ppm for the methoxy groups, 6.0 ppm for the H of pyrimidine and 7.6 ppm for the hydrogens on thiophene. The infrared absorption spectrum showed absorption peaks at 1730 and 1700 cm-1 consistent for the two carbonyl peaks in the desired product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:25].O>C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH:12]=[O:25]
Reactant: N#CCC1COc2ccccc2O1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Product: O=CCC1COc2ccccc2O1

Procedure:
The starting material is prepared as follows: To the solution of 20 g of 1,4-benzodioxan-2-yl-acetonitrile in 200 ml of benzene is added dropwise 71 ml of a 1.6 N solution of diisobutyl aluminum hydride in benzene while stirring at 10°. After 6 hours 50 ml of methanol are added, followed by 200 ml of water. The organic layer is separated, dried and evaporated, to yield the 1,4-benzodioxan-2-yl-acetaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16](Cl)=[N:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[C:14]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:15][C:16]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:17][CH:18]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Oc2ncc(Br)c(Oc3ccc(F)cc3F)n2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
2,4-Difluorophenol (22 mL, 241.34 mmol) was dissolved in 140 mL of dry THF and cooled to 0° C. Sodium hydride (9.43 g, 235.85 mmol, 60% suspension in oil) was added in portions, and the reaction mixture was stirred for 30 minutes at 0° C. 5-Bromo-2,4-dichloro-pyrimidine (25.0 g, 109.7 mmol) was added in portions over 10 minutes, and the reaction mixture was allowed to warm to room temperature and was stirred overnight at room temperature. The reaction was quenched by addition of 30 mL saturated aqueous ammonium chloride and 100 mL of water. The aqueous mixture was extracted three times with 100 mL EtOAc, and the combined organic layers were dried (MgSO4), filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by FLASH chromatography (2% to 6% EtOAc/Hexanes. The resulting solid was recrystallized from diethyl ether/hexanes to afford 12.6 g of 5-bromo-2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine as a white solid. Mass Spec. M+H=416.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@H:24]5[O:29][CH2:28][CH2:27][NH:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40]Br>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@H:24]5[O:29][CH2:28][CH2:27][N:26]([CH2:40][CH2:39][O:38][CH3:37])[CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CNCCO1
Product: COCCN1CCO[C@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-4-(2-methoxyethyl)morpholin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-morpholin-2-ylmethyl]1,3-thiazolidine-2,4-dione (Example 183) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:8]=[CH:9][C:2]1=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH:6]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2sccc2c1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2sccc2c1
Yield: 40.9 %

Procedure:
To a solution of 5-bromobenzo[B]thiophene (9.4 mmol) in 100 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° C. was added 5.9 mL of a 1.6 M hexanes solution of n-butyllithium (9.4 mmol). The 5bromobenzo[B]thiophene was synthesized by procedures well known in the art. See, European Patent Application 355827 (published Feb. 28, 1990). The reaction was warmed to 0° C. and stirred for 30 minutes. Sulfur dioxide gas was bubbled through this mixture for 20 minutes at 0° C., and the reaction concentrated under vacuum. The residue was dissolved in 50 mL of water. Sodium acetate (74 mmol) and hydroxylamine-0-sulphonic acid (24 mmol) were added to this solution and this reaction was stirred at room temperature for 1.5 hours. This mixture was diluted with 50 mL of water and the reaction extracted with ether (3×50 mL). The combined organic layer was extracted with 1 N sodium hydroxide (3×50 mL), the organic layer discarded, and the aqueous layer acidified with about 150 mL of 1 N hydrochloric acid. The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography with 30% acetone in hexanes with 1% acetic acid on silica gel to obtain 340 mg of 5benzo[B]thiophenesulfonamide. The sulfonamide (1.6 mmol) was reacted with 4-chlorophenylisocyanate (1.9 mmol) as described in Method A above to obtain 240 mg of the title product as a solid. 1H NMR (CD3SOCD3): δ9.04 (s, 1 H), 8.16 (s, 1 H), 8.08 (d, J =6 Hz, 1 H), 8.04 (d, J =6 Hz, 1 H), 7.52 (d, J =6 Hz, H), 7.46 (m, 2 H), 7.42 (d, J =9 Hz, 2 H), 7.30 (d, J =Hz, 2 H).