Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: NC(=O)NCCCl
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OCCNC(N)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-chloroethylurea.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:15][CH2:16][CH3:17].[Na+].O>C(O)C>[CH:12]1([C:4]2[C:5]3[N:6]([C:8]([NH2:11])=[N:9][N:10]=3)[N:7]=[C:2]([O:15][CH2:16][CH3:17])[CH:3]=2)[CH2:14][CH2:13]1
Reactant: Nc1nnc2c(C3CC3)cc(Cl)nn12
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C2CC2)c2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
6-Chloro-8-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.010, 77 mg) was initially charged in ethanol (10 ml) while stirring at RT and admixed with sodium ethoxide (67 mg). After stirring for 4.5 h, the mixture was left to stand overnight and then the solvent was drawn off. The residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 91 mg of the title compound were obtained.
Reaction SMILES: [C:1]([Si:5]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:36]([OH:40])(=[O:39])[CH:37]=[CH2:38]>C1(C)C=CC=CC=1>[C:36]([O:40][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 41.4 g (0.20 mol) of tert-butyldiisopropylchlorosilane, 60 ml of By toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 15.9 g (0.22 mol) of acrylic acid was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for 2 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 42.9 g of a fraction having a boiling point of 80-83° C./0.27 kPa.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:22]([NH2:24])=O>>[OH:8][C:7]1[C:6]2[C:5]3[CH2:12][CH:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=[CH:22][N:24]=1
Reactant: CCOC(=O)CC1CCc2sc(N)c(C(=O)OCC)c2C1
Reactant: NC=O
Product: CCOC(=O)CC1CCc2sc3ncnc(O)c3c2C1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of ethyl 2-amino-5-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (20.68 g, 66.41 mmol, 1.00 equiv) in 100 mL of formamide was stirred overnight at 180° C. in an oil bath. After the starting material disappeared, the reaction was cooled to room temperature and quenched with water, extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) to afford ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (10.10 g, 52%) as yellow oil. LC-MS (ES, m/z): 293 [M+H]+.
Reaction SMILES: [CH3:1][N:2](C)/C=N/[H].[Br:7][C:8]1[CH:9]=[C:10]([CH3:17])[C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.CC([O-])(C)C.[K+].Cl>C1COCC1>[Br:7][C:8]1[CH:13]=[N:12][C:11]2[C:14](=[O:16])[NH:2][CH:1]=[CH:17][C:10]=2[CH:9]=1
Reactant: Cc1cc(Br)cnc1C(=O)O
Reactant: [H]/N=C/N(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1[nH]ccc2cc(Br)cnc12
Temperature: 25 °C

Procedure:
5-Bromo-3-methyl-pyridine-2-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamine (2.5 g, 9.25 mmol) was dissolved in THF (20 ml). KOtBu (1.565 g, 13.05 mmol) in THF (30 ml) was added dropwise and the reaction mixture was heated to reflux for 3 h and then cooled to rt. The pH was adjusted to 7 with concentrated HCl. The reaction mixture was concentrated. The brown solid obtained was triturated with water (10 ml). The solid thus obtained was collected by filtration (2 g, 8 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37]C)=[O:36])=[CH:31][C:30]=1[CH3:39])=[O:5])C.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[C:44]([Cl:48])=[CH:43][C:42]=1[OH:49].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]3[CH2:15][CH2:16][CH2:17][O:49][C:42]2[CH:43]=[C:44]([Cl:48])[C:45]([Cl:47])=[CH:46][C:41]=2[Cl:40])=[C:30]([CH3:39])[CH:31]=1)([OH:37])=[O:36]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC)cc3C)cccc2c1CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)ccc1-c1cccc2c(CCCOc3cc(Cl)c(Cl)cc3Cl)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 127C (60 mg) in DMF (1 mL) was added 2,4,5-trichlorophenol (43 mg) and Cs2CO3 (500 mg). The mixture was stirred at room temperature overnight, diluted with ethyl acetate (150 mL), and washed with water and brine. After drying over Na2SO4, the combined organic layers were concentrated, and the concentrate was saponified with LiOH as described in EXAMPLE 65B. 1H NMR (300 MHz, DMSO-d6) δ 12.92 (m, 1H), 10.88 (s, 1H), 7.89 (s, 1H), 7.82 (m, 2H), 7.38 (s, 1H), 7.32 (d, 1H), 7.10 (m, 2H), 4.13 (t, 2H), 3.25 (t, 2H), 2.13 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCOCC1.ClCCl>[CH2:14]([O:21][C:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Aminomethyl)benzoic acid 15.1 g (100 mmol) was dissolved in 200 mL dioxane and 100 mL 1.000 N NaOH and cooled in a 0° C. ice bath. The mixture was treated dropwise with benzylchloroformate 14.3 mL (100 mmol) followed by the dropwise addition of 100 mL of 1.000 N NaOH. The mixture was stirred at room temperature for 18 hours. The mixture was neutralized by adding 100 mL of 1.000 N HCl followed by dilution with dichloromethane. A white solid precipitated out which was filtered. The solid was dried in vacuo to afford 10.8 g (38.9%). 1H NMR (300 MHz, DMSO-d6): δ 4.24 (d, 2H, J=6.2 Hz); 5.01 (s, 2H); 7.31-7.34 (m, 7H); 7.84-7.88 (m, 3H); 12.85 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C>[Br:18][C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[CH2:2][Cl:1]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=c1[nH]c(CCl)c(Br)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a solution of 6-(chloromethyl)uracil (2.0 g, 12.5 mmol) in DMF (15 mL) at 0° C. was added NBS (recrystallized, 2.44 g, 13.7 mmol). The mixture was stirred at 0° C. for 1.5 h, and then quenched by ice water. The precipitate was collected by filtration and washed with AcOH and water to give the title compound (2.35 g, 69%) as a white solid. 1H NMR (DMSO, 500 MHz) δ 1.66 (s, 1H), δ 11.61 (s, 1H), δ 4.47 (s, 2H). MS (Multimode, M+H+) C5H5BrClN2O2, calcd. 238.9. found 238.9.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)O)[CH2:10][CH2:9]1.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)[CH2:10][CH2:9]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 ml (9.82 mmol) of trifluoroacetic acid was added to 1.77 g (8.19 mmol) of the compound from Example 149A and 1.45 g (8.19 mmol) of the compound from Example 8A in 91 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 890 mg (29% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28]N=2)=[CH:4][CH2:3]1.F[C:32](F)(F)S(OC1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][CH:32]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 328.0 mg (0.685 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 186.8 mg (1.37 mmol) of zinc chloride 37.1 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiothiophene (prepared by the addition of 65.9 mg (0.69 ml, 1.03 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 86.5 mg (1.03 mmol) of thiophene in 1.0 mL of THF).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C@@H:12]([OH:28])[C@@H:13]2/[CH:16]=[CH:17]/[C@@H:18]([OH:27])[C:19]([CH3:26])([CH3:25])[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[O:9]1)([OH:3])=[O:2].[N+](=[CH2:31])=[N-]>C(Cl)Cl>[CH3:31][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C@@H:12]([OH:28])[C@@H:13]2/[CH:16]=[CH:17]/[C@@H:18]([OH:27])[C:19]([CH3:26])([CH3:25])[CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[O:9]1)=[O:3]
Reactant: C=[N+]=[N-]
Reactant: CC(C)=CCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)O)O[C@H]2C[C@H]1O
Solvent: ClCCl
Product: COC(=O)CCCC[C@@H]1C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)(C)CC=C(C)C)[C@H](O)C[C@@H]2O1

Procedure:
A solution of 100 mg. of the carboxylic acid prepared in Example 30 in 10 ml. of methylene chloride is combined dropwise with an ethereal diazomethane solution at 0° until the yellow coloring is permanent. After 5 minutes the mixture is evaporated under vacuum and the residue filtered with methylene chloride/2% isopropanol over silica gel, thus obtaining 95 mg. of the title compound as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13]CC(=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.Cl.[CH2:20]1[CH2:24][O:23]C[CH2:21]1>C(O)(C)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:24](=[O:23])[C:20]([CH3:21])([CH3:17])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CI
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: -6.5 °C
Reaction time: 1 h

Procedure:
1-Benzyl-4-piperidone (100 gm, 0.53 mol) diluted with 100 ml THF was added to a suspension of 60% NaH (42 g, 1.05 mol) in 700 ml THF at −10 to −5° C. The mixture was stirred for 1 hour and methyl iodide (150 gm, 1.06 mol) diluted in 50 ml THF was added, maintaining the temperature between −3 to −10° C. The resultant mixture was stirred. Ethyl acetate (800 ml) was added to the reaction mixture followed addition of 300 ml water. The organic layer was separated washed with 2×300 ml water and concentrated under vacuum to obtain a syrup. The syrup was triturated with 200 ml hexane. the mass was filtered at room temperature over celite and the filtrate concentrated to afford a 121 gm of crude compound. The crude compound upon high vacuum distillation afforded 85 g distillate. To the distillate (50 gm) was charged 50 ml of concentrated hydrochloric acid. The suspension was stirred for 15 minutes and hydrochloric acid was evaporated under vacuum to obtain a thick residue. Isopropanol (50 ml) was added to this residue and was evaporated under vacuum to obtain a solid. The solid was dissolved in 200 ml isopropanol under reflux and stirring, and cooled under stirring to effect crystallization. The crystalline solid was filtered under suction at 20-30° C. to give a white crystalline compound as hydrochloride salt of 1-benzyl-3,3-dimethyl-4-piperidone. The solid was dissolved in 100 ml water and made alkaline with aqueous ammonia solution to pH 10-11. Alkaline aqueous phase was extracted with 50 ml chloroform thrice. Combined organic extract was washed with water, dried over sodium sulfate and then evaporated under vacuum to afford 28 g (80%) compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]([OH:14])(=[O:13])[C:11]#[CH:12].[CH:15]1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH3:15][O:13][C:10](=[O:14])[C:11]#[C:12][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COc1cccc(Br)c1
Reactant: C#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C#Cc1cccc(OC)c1
Yield: 925.4 %

Procedure:
The general procedure described in Example 27 was used with 3-bromoanisole (0.063 mL, 0.50 mmol), propiolic acid (added at 0° C.) (0.050 mL, 0.65 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.0 mL), 12 h, 60° C. The product was isolated as a colorless oil (66 mg, 69%). 1H NMR (400 MHz, CDCl3) δ: 7.28 (t, 1H, J=7.6 Hz, 8.4 Hz), 7.17 (dt, 1H, J=1.2 Hz, 7.6 Hz), 7.09 (m, 1H), 7.00 (qd, 1H, J=1.2 Hz, 2.4 Hz, 8.4 Hz), 3.84 (s, 3H), 3.80 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 159.4, 154.6, 129.9, 125.6, 120.5, 117.7, 117.6, 86.6, 80.2, 55.5, 52.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]([OH:31])CO)[N:11]=1>CC(C)=O.O.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=[O:31])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CCC(O)CO)c2nc(Nc3ccccc3)ncc12
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 114 mg (0.3 mmol) of 4-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butane-1,2-diol 34 (Example 2) in 10 mL of acetone and 7 mL of water was treated with 585 mg (2.7 mmol) of NaIO4. The resulting tan slurry was stirred at room temperature for 6 h. The reaction mixture was diluted with CH2Cl2, filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2 (75 mL) and washed with water (50 mL). The aqueous layer was extracted with more CH2Cl2 (2×75 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated to give the title compound 36, which was used without further purification. 1H-NMR (CDCl3) δ 2.27 (s, 6H), 3.05 (t, J=6.7 Hz, 2H), 4.52 (t, J=6.7 Hz, 2H), 5.30 (s, 1H), 5.89 (s, 1H), 7.06 (t, J=7.6 Hz, 1H), 7.13-7.19 (m, 3H), 7.34 (t, J=7.7 Hz, 2H), 7.42 (s, 1H), 7.64 (d, J=7.7 Hz, 2H), 9.89 (s, 1H). Mass Spectrum (ESI) m/e=387.2 (M+1).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([N:8]=C=O)[CH2:6][C@@H:5]([NH:11][S:12]([CH:15]2[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:4]1)[CH3:2].[ClH:18].CCOCC.CCOC(C)=O>O>[ClH:18].[NH2:8][C@@H:7]1[C@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([NH:11][S:12]([CH:15]2[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:6]1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N=C=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide (0.972 g, 3.76 mmol) and aqueous HCl (6 N, 31.4 mL, 188 mmol) was heated at about 100° C. for about 60 h. Aqueous HCl (12 N, 5 mL) was added and the reaction mixture was heated at about 100° C. for about 18 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The residue was treated with Et2O (10 mL) and EtOAc (10 mL). The mixture was concd under reduced pressure. Water (5 mL) was added and the sample was lyophilized to give N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropane-sulfonamide hydrochloride (0.859 g, 85%) as a white solid: LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z 233 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH2:8][CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].C(=O)([O-])N.[K+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[S:21]>CC(C)=O>[CH2:23]([O:22][P:20]([O:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:1]([O:3][CH3:4])=[O:2])[C:10]=2[N:11]=1)([O:25][CH2:26][CH3:27])=[S:21])[CH3:24]
Reactant: COC(=O)C1CCCc2sc(=O)[nH]c21
Reactant: CCOP(=S)(Cl)OCC
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCCC2C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A mixture of 4 g of 4-carbomethoxy-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one, 3 g of potassium carbamate and 50 ml of acetone was refluxed for 1 hour and after the addition of 4 g of O,O-diethyl chlorothiophosphate, the mixture was refluxed for another hour. The mixture was stirred for 18 hours at room temperature and the mineral salts formed were filtered off. The filtrate was distilled to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.5 g of 2-(diethoxythiophosphoryloxy)-4-carbomethoxy-4,5,6,7-tetrahydrobenzothiazole with a refractive index nD26 = 1.5261.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl.O>CN(C=O)C>[Cl:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]([CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Cl)ncc2ncn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material, 6-chloro-3H-pyrido[3,4-d]pyrimidin-4one (710 mg, 3.92 mmol, prepared according to J. Chem. Soc., Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20 ml). Cs2CO3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added subsequently. The reaction is stirred at room temperature overnight, poured into water. After extraction with CH2Cl2, the organic layer is washed with H2O and brine, dried (Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flash chromatography to give the product as a white solid.
Reaction SMILES: ClC1C=CC(N[C:9]([NH:13][C@@H:14]2[C:19]3[CH:20]=[C:21]([P:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])[O:25][CH3:26])[CH:22]=[CH:23][C:18]=3[O:17][C:16]([CH3:35])([CH3:34])[C@H:15]2[OH:36])=[N:10][C:11]#[N:12])=CC=1.N[C@@H:38]1[C:43]2C=C(P(C3C=CC=CC=3)(=O)OC)C=CC=2O[C:40](C)(C)[C@H:39]1O.CN(C=[O:65])C>C(OCC)(=O)C>[OH:36][C@H:15]1[C@H:14]([NH:13][C:9]([NH:10][C:11]2[CH:40]=[CH:39][CH:38]=[CH:43][N:12]=2)=[O:65])[C:19]2[CH:20]=[C:21]([P:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])[O:25][CH3:26])[CH:22]=[CH:23][C:18]=2[O:17][C:16]1([CH3:34])[CH3:35]
Reactant: CN(C)C=O
Reactant: COP(=O)(c1ccccc1)c1ccc2c(c1)[C@@H](N)[C@H](O)C(C)(C)O2
Reactant: COP(=O)(c1ccccc1)c1ccc2c(c1)[C@@H](NC(=NC#N)Nc1ccc(Cl)cc1)[C@H](O)C(C)(C)O2
Solvent: CCOC(C)=O
Product: COP(=O)(c1ccccc1)c1ccc2c(c1)[C@@H](NC(=O)Nc1ccccn1)[C@H](O)C(C)(C)O2
Reaction time: 6 h

Procedure:
To a solution of the title G compound of Example 1 ((3S-trans)-(4-Amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)phenylphosphinic acid, methyl ester (300 mg, 0.86 mmol) in 3 mL of anhydrous DMF was added the title A compound (334 mg, 1.29 mmol) at room temperature. The reaction mixture was stirred for 6 h then a second 334 mg portion of the title A compound was added. After an additional 18 h a third 334 mg portion of the title A compound was added. The mixture was stirred for 6 h then diluted with 25 mL of ethyl acetate, washed with three-25 mL portions of 1M aq NaOH solution, dried (sodium sulfate) and concentrated in vacuo to give an oil. The crude oil was purified by flash chromatography (Merck silica, 18×3.0 cm, 1:14 methanol/methylene chloride) to afford the title compound as a solid white foam (128 mg, 0.27 mmol, 32%).