Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(CCC(O)=O)(=O)=O)C=CC=CC=1.O[C:16]1[C:24]2[N:23]=NN[C:20]=2C=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[N:33]2[CH2:36][CH:35]([NH:37]C(=O)C3C=CC(S(C)(=O)=O)=CC=3)[CH2:34]2)=[CH:28][CH:27]=1>CN(C)C=O.ClCCl>[CH:32]([N:33]=[C:34]=[N:23][CH:24]([CH3:20])[CH3:16])([CH3:50])[CH3:29].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[N:33]2[CH2:34][CH:35]([NH2:37])[CH2:36]2)=[CH:28][CH:27]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CS(=O)(=O)c1ccc(C(=O)NC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)cc1
Agent: O=C(O)CCS(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N=C=NC(C)C
Product: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
By carrying out the operation according to the procedure of Example 31, starting with 58.5 mg of 3-phenylsulfonylpropionic acid, 26.4 mg of hydroxybenzotriazole in solution in 0.5 cm3 of dimethylformamide, 0.0302 cm3 of diisopropyl-carbodiimide, a solution of 30 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 0.5 cm3 of anhydrous dichloromethane, and 3 cm3 of anhydrous dichloromethane, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methanesulfonylbenzamide is obtained in the form of a lacquer [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.71 (t, J=7.5 Hz: 2H); 2.86 (mt: 2H); from 3.40 to 3.55 (mt: 4H); 4.26 (s: 1H); 4.45 (mt: 1H); 6.22 (broad d, J=7.5 Hz: 1H); from 7.20 to 7.35 (mt: 8H); 7.59 (broad t, J=7.5 Hz: 2H); 7.69 (tt, J=7.5 and 1.5 Hz: 1H); 7.93 (broad d, J=7.5 Hz: 2H)].
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>C(#N)C>[CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][Cl:13]
Reactant: O=c1cc(CO)occ1O
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=c1cc(CCl)occ1O
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A 2-litre 3-neck round bottom flask was equipped with a mechanical stirrer. The flask was charged with kojic acid (0.25 kg, 1.759 mol) and 750 ml acetonitrile at 0° C. The kojic acid was insoluble in acetonitrile and stayed as a suspension. Thionyl chloride (140 ml, 1.919 mol) was added dropwise via a dropping funnel at ice bath temperature. The solid slowly dissolved to give a red clear solution. After 15 minutes, a white solid appeared. After 3 hrs at 0° C., the insoluble solid was filtered. The solid was filtered by suction filtration. The solid was mixed with water (0.5 L) and then filtered. The acetonitrile mother liquor was reduced to 15% of the original volume and filtered. The solid was washed with water (200 ml) and then acetonitrile (50 ml). The combined solid was dried to constant weight (269 g, 95.2% yield). M.p. 166-168° C. [lit value 166-167° C.]. 1H-NMR (DMSO-d6) δ: 4.66 (s, 2H, CH2Cl), 657 (s, 1H, CH), 8.12 (s, 1H, CH), 9.3 (br. s, 1H, OH).
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[N+]([O-])(OCCC(C)C)=O.[CH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:11]1([C:9]2[O:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Reactant: c1ccccc1
Agent: CC(C)CCO[N+](=O)[O-]
Product: c1ccc(-c2ccc3nc(-c4ccccc4)oc3n2)cc1

Procedure:
A mixture of 180 mg. of 5-amino-2-phenyloxazolo[ 5,4-b]pyridine, 10 ml. of benzene and 0.2 ml. of isoamyl nitrate was refluxed for 11/2 hours. The hot solution was filtered and concentrated to dryness. The residue was extracted with ether and the extract was filtered through aluminum oxide and concentrated to dryness. The crystalline residue was recrystallized from ethyl acetate to give 2,5-diphenyloxazolo[ 5,4-b]pyridine, m.p. 151°-152° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: COC(=O)c1ccsc1N
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2sccc12
Temperature: 190 °C
Yield: 23 %

Procedure:
Methyl 2-aminothiophene-3-carboxylate (10 g, 64 mmol) was charged with formamide (50 mL). The reaction was heated at 190° C. under nitrogen for 3 hours, then cooled to ambient temperature. The resulting slurry was poured into 125 mL of water and extracted with chloroform:isopropyl alcohol mixture (2 times). The solution was concentrated and triturated to afford the title compound (2.25 g, 23%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:21].N1C=CN=C1.[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].O>CN(C)C=O.C(OCC)(=O)C>[Si:31]([O:20][CH2:19][CH2:18][C:14]1[C:13](=[O:21])[N:12]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 g (346 mmol) of the compound from Example 61A (alternative synthesis) and 30.7 g (450 mmol) of imidazole are dissolved in 1 l of anhydrous N,N-dimethylformamide. A solution of 117 g (416 mmol) of tert-butyl(chloro)diphenylsilane in 150 ml of N,N-dimethylformamide is added dropwise, and the mixture is stirred at RT for 3 h. Water and ethyl acetate are then added, the phases are separated and the organic phase is washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is triturated with petroleum ether/diethyl ether (10:1). After filtration, the residue is washed with petroleum ether and then air-dried. This gives 150 g (82% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>O.CC(O)=O.[Fe]>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N)cnc1Cl
Yield: 88.7 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (3.2 g, 18.5 mmol; Maybridge Chemical Co.) was dissolved in a mechanically stirred solution of H2O/HOAc (60 mL, 5:1). Iron powder was added over a 5 h period, maintaining the temperature below 40° C., and stirring was continued until starting material had be consumed. The reaction mixture was filtered, and the filter cake was washed with EtOAc. The aqueous filtrate was extracted with EtOAc, and the combined organic fractions were washed with saturated NaHCO3 solution, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford 5-amino-2-chloro-3-methylpyridine as an orange solid (2.34 g, 89%): MS (CI/NH3) m/z: 143 (M+H)+ ; NMR (DMSO-d6, 300 MHz) δ 2.17 (s, 3H), 5.40 (br s, 2H), 6.90 (d, J=2.2 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)C=CC=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1C(c2cccc(OC)c2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Solvent: CCO
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
Ethyl (1RS,2RS,3SR)-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was shaken on a Parr hydrogenator at 50 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced preqssure to afford the title compound (43 mg, 94%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (25.00 g, 116 mmol) in THF (250 mL) at 0° C. was added borane dimethyl sulfide complex (2.0 M in THF, 87 mL, 174 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. The mixture was cooled to 0° C. and quenched by dropwise addition of MeOH (100 mL) within 15 minutes. The mixture was stirred at 0° C. for 15 minutes and concentrated. The residue was taken up in EtOAc and washed with 1 M HCl, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated to give INT 29.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[N:14]1([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-Fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (M−H, 100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2.[F:22][C@@H:23]1[CH2:27][N:26]([C:28](=[O:40])[CH2:29]OS(C2C=CC=CC=2)(=O)=O)[C@H:25]([C:41]([NH2:43])=[O:42])[CH2:24]1.O>CN(C)C=O>[CH2:20]([O:19][C:17]([C:12]12[CH2:11][CH2:10][C:9]([NH:8][CH2:29][C:28]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[C:41]([NH2:43])=[O:42])=[O:40])([CH2:16][CH2:15]1)[CH2:14][CH2:13]2)=[O:18])[CH3:21]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
Potassium carbonate (277 mg) was added to a solution of ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (319 mg) in N,N-dimethylformamide (1.8 mL), followed by stirring at an inner temperature of 40° C. for 30 minutes. (2S,4S)-4-Fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carboxamide (295 mg) was added thereto, followed by stirring at the same temperature for 1 hour. Water (5.4 mL) was added to the reaction solution, followed by stirring at an inner temperature of from 5 to 10° C. for 30 minutes. The precipitate were collected by filtration, washed with cold water (4 mL) and then blast-dried at an outer temperature of 40° C., thereby obtaining white crystals of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (obtained amount: 247 mg, yield: 75%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC.O1CCCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[O:18][C:13]([O:19][CH2:20][CH3:21])=[CH:14][CH:15]([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=CC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 1 liter flask was equipped with a mechanical stirrer, a reflux condenser, an addition funnel, nitrogen inlet, and thermometer. The glassware was dried carefully and charged with 225 ml of tetrahydrofuran, 30.36 g (0.300 mol) of diisopropylamine, and cooled to 0° C. Over a 30 minute period, 190 ml (0.300 mol) of 1.6 M n-butyl lithium in hexane was added. The reaction mixture was stirred at 0° C. for 15 min., then cooled to -76° C. and 39.06 g (0.300 mol) of ethyl isovalerate added dropwise over ~15 min. When addition was complete, the reaction mixture was stirred for 15 min. at -76° C., then 82 ml (0.88 mol) of chlorotrimethylsilane added dropwise. When addition was complete, the Dry Ice-acetone bath was removed and the reaction mixture stirred for 11/2 hrs. while coming up to room temperature.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCCCCC.O1CCCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:7]2[C:16]3[O:15][CH2:14][CH2:13][O:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccc2c1OCCO2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cccc3c2OCCO3)CCN(Cc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
23.3 ml of a 1.6 M solution of butyllithium in hexane are added dropwise to a solution, previously cooled to -60° C., of 8 g of 5-bromo-1,4-benzodioxane in 400 ml of tetrahydrofuran. When the addition is complete, the mixture is stirred at -60° C. for 5 minutes and a solution of 8 g of 1-benzylpiperid-4-one in 100 ml of tetrahydrofuran is then added dropwise. The mixture is stirred for 2 hours at -40° C. and then for 2 hours at ambient temperature before hydrolyzing using 80 ml of water.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13]SC)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.C(O)C>[OH-].[K+].[Ni]>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CSCc1c(C(F)(F)F)ccc(Cl)c1N
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Dissolve 2 g. of 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride in 50 ml. of 90% ethanol which is 1N in potassium hydroxide. Add 2 teaspoonsful of Raney nickel (W-2). Stir at 70° C. for 3 hours, cool and filter. Add 50 ml. of water and extract three times with hexane. Dry the combined organic extracts and evaporate to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N+:19]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a stirred solution of (3RS,4SR)-1-benzyl-3-nitro-4-phenyl-pyrrolidine (1.0 g, 3.54 mmol) in EtOAc (50 ml) was added in one portion SnCl2.2H2O (3.99 g, 17.70 mmol). The reaction mixture was then heated at reflux for 2 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (100 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 0.72 g (80%) of (3RS,4SR)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine as a light yellow oil. The product was then used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[CH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCOCC3)c21

Procedure:
Using Method C above, 3-(4-morpholinyl)-1-propyne (63.6 mg, 0.51 mmol) (prepared according to H. Kano et al., J. Med. Chem. 10:411-418 (1967)) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(4-morpholinyl)-1-propynyl]-2H-indol-2-one. (Yield 40 mg, 54%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[N:6]=1)[CH2:2][CH3:3].O.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:8]1[C:7]([OH:12])=[N:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=1[OH:11])([O-:16])=[O:15]
Reactant: CCCSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 2-(propylthio)pyrimidine-4,6-diol (3 g, 16.11 mmol, 1.00 equiv.) in nitric acid (65%) (10 mL) was stirred at ambient temperature for about 2 hours. After adding water (10 mL), the mixture was stirred at about 0° C. for about 30 minutes. The resulting solids were collected by filtration to afford the title product as a yellow solid (1.8 g; yield=48%). 1H NMR (300 MHz, DMSO-d6) δ: 3.17 (t, J=7.2 Hz, 2H), 1.62-1.75 (m, 2H), 0.95-1.02, (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=1.[O-]CC.[Na+].CC(O)=O>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=[C:8]([Cl:19])[C:7]=1[N:6]1[C:2]2=[N:1][C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:24][C:22](=[O:23])[C:3]2=[C:4]([CH2:20][CH3:21])[NH:5]1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(-c2c(Cl)cc(C(=O)O)cc2Cl)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 75.1 %

Procedure:
Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ethoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)−.
Reaction SMILES: [Na].[F:2][C:3]1[C:8]([F:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[N:15]=[C:16]([NH:19][C:20](=[O:35])[CH2:21][C:22]2[C:30]3[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=3[S:24][N:23]=2)[S:17][CH:18]=1.[P:36]([O-:40])([O-:39])([O-:38])=[O:37].[CH3:41]C(C)([O-])C.[Na+]>C1COCC1.CCCCCC>[P:36]([OH:40])([OH:39])([O:38][CH2:41][N:15]1[C:14]([C:4]2[CH:5]=[CH:6][C:7]([C:10]([F:12])([F:11])[F:13])=[C:8]([F:9])[C:3]=2[F:2])=[CH:18][S:17][C:16]1=[N:19][C:20](=[O:35])[CH2:21][C:22]1[C:30]2[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=2[S:24][N:23]=1)=[O:37]
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4F)cs3)nsc2n(C)c1=O
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(C(F)(F)F)c(F)c4F)n3COP(=O)(O)O)nsc2n(C)c1=O

Procedure:
Sodium salt of N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide: The title compound was prepared according to the general procedure as described in step 1 of method B for the preparation of phosphate derivatives by the reaction of N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide (1.95 g, 3.771 mmol) with sodium-tert-butoxide (0.362 g, 3.771 mmol) in dry THF (12 ml) and hexane (40 ml) to yield 2.00 g of product as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 3.22 (s, 3H), 3.48 (s, 3H), 3.98 (s, 2H), 7.25 (s, 1H), 7.59 (t, J=8.1 Hz, 1H), 8.03 (t, t, J=7.2 Hz, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1C[O:12][CH2:11]C1>>[N:7]1[C:11](=[O:12])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: C1CCOC1
Reactant: Nc1ccccc1N
Product: O=C1N=c2ccccc2=N1
Reaction time: 16 h

Procedure:
A solution of phenylene diamine 6.48 g in dry THF (150 ml) was cooled to 5° C. A suspension of 1,1-carbonyldiimidazole (10.7 g) in THF (100 ml) was added to this solution over 15 minutes keeping the temperature below 10° C. The mixture was stirred for 16 hours and the resultant solid was collected and dried to give the title compound (4.5 g); NMR: 6.9 (s, 4H), 10.5 (s, 2H); MS (ESP+): 135 (M+H)+.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[C:24]([CH3:26])[CH:25]=1.C1C(=O)N([Br:38])C(=O)C1>ClCCl>[Br:38][CH2:26][C:24]1[CH:23]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(CC(=O)O)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)cc(CBr)c1
Temperature: 25 °C

Procedure:
Dibenzoyl peroxide (0.5 g) was added to a stirred mixture of 2-(3-fluoro-5-methylphenyl)acetic acid (5.95 g) and NBS (6.93 g) in dichloromethane (120 mL). The resultant mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and then washed twice with water. The organic layer was dried, filtered and the solvent concentrated under reduced pressure. The crude product was purified by flash silica chromatography using 1% acetic acid and 17% ethyl acetate in isohexane as solvent. Fractions containing the product were concentrated to dryness to afford the subtitled compound. Yield 6.50 g.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)cc1F
Yield: 76.8 %

Procedure:
In a fashion similar to that for preparation 13, 4-bromo-2-fluorobenzaldehyde (5.00 g, 24.6 mmol), hydroxylamine hydrochloride (2.05 g, 29.6 mmol), NaOH (4.92 g, 61.5 mmol; in a 50% by weight solution), ethanol (15 ml), water (15 ml), and ice (30 g) gave the title compound (4.12 g, 77%) which was used without purification.