Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl>[Br:31][C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=3)=[N:9][C:10]2=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1

Procedure:
1.5 g 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 1) and 0.9 g NBS are refluxed in 30 ml chloroform for 1 h. The solvent is removed by distillation and the crude product is purified by column chromatography (dichloromethane/methanol).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:19]>>[Br:12][C:5]1[CH:4]=[CH:3][C:2]([F:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: Nc1ccc(Br)c2ccncc12
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: Fc1ccc(Br)c2ccncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8-amino-5-bromoisoquinoline in 48% HBF4 (30 mL) at 0° C. was slowly added an aqueous (10 mL) solution of NaNO2 (172 mg, 2.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and was then concentrated under reduced pressure to give a dark residue. The dark residue was heated to 150° C. for 16 h. The resulting dark oil was cooled to 23° C., quenched with ammonium hydroxide and extracted with DCM. The organic solution was concentrated and the resulting dark solid was recrystallized from EtOAc/Hexanes. The desired product (100 mg) was in the mother liquor while the by-product was filtered away as a solid. LCMS showed an m/z of 228.0/226.0 with a retention time of 1.318 min, method [1].
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1.[OH-].[K+].I[CH3:16].Cl>O.C(O)C>[CH3:16][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: CI
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c(SC)nc2c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
First, 18.00 g (100 mmol) of 2-mercapto-5-methoxy-1H-benzimidazole, 16.83 g (300 mmol) of potassium hydroxide, 75 ml of ethanol, and 50 ml of water were added to a 3-necked flask (300 ml volume) equipped with a thermometer, a mechanical stirrer and a dropping funnel, and cooled to 5° C. Next, 15.00 g (105 mmol) of iodomethane was added dropwise to this solution over a period of 30 minutes while keeping internal temperature at 10° C. or lower. Then the solution was agitated for 2 hours at 10° C. or lower. The reaction solution was neutralized with an aqueous 2N hydrochloric acid solution, then the ethanol was removed under reduced pressure to precipitate a colorless solid. This solid was filtered and dried under reduced pressure to give 19.19 g of 2-methylthio-5-methoxy-1H-benzimidazole (yield of 98.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1=CCNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide and 2,5-dihydropyrrole, TBTU, and triethylamine in DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:25]([N:27](CC)CC)C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:27][CH3:25])[CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (400 mg, 1.6 mmol) in dimethylformamide and dichloromethane was treated with oxalyl chloride (0.16 ml, 1.9 mmol) drop wise at room temperature followed by stirring at same temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane, cooled to 0° C. and methylamine hydrochloride (118 mg, 1.7 mmol) was added followed by the drop wise addition of triethylamine (0.33 ml, 2.4 mmol) at the same temperature. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour and concentrated under vacuum. The residue was treated with ice-cooled aqueous sodium bicarbonate solution (5%). The precipitated solid was filtered, washed with water, and dried to yield methyl 2,6-dichloro-4-(methylcarbamoyl)benzoate (340 mg, 70%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH2:30][CH2:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[O:28]1[CH2:29][CH2:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Reactant: c1cc2c(c(OC[C@@H]3CO3)c1)CCO2
Solvent: CO
Product: O[C@H](COc1cccc2c1CCO2)CN1CCC(c2ccc3cc(F)ccc3c2)CC1
Yield: 26.1 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)piperidine (0.075 g, 0.327 mmol) and (S)-(+)-4-(oxiranylmethoxy)-2,3-dihydrobenzo[b]furan (0.063 g, 0.327 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the title compound as a white amorphous solid (0.036 g, 26%). FDMS m/e=422 (M++1). [α]D=21.65 (c 0.508, methanol). C26H28FNO3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1.[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])=[C:13]=[S:14]>O1CCCC1>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:12][C:13]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1)=[S:14])([O-:23])=[O:22]
Reactant: CCOC(=O)N1CCC(N)C1
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 15.8 parts of ethyl 3-amino-1-pyrrolidinecarboxylate, 18 parts of 1-isothiocyanato-2-nitrobenzene and 180 parts of tetrahydrofuran was stirred for 1 hour at room temperature. The reaction mixture was evaporated, yielding 34 parts (100%) of ethyl 3-[[[(2-nitrophenyl)-amino]thioxomethyl]amino]-1-pyrrolidinecarboxylate as a residue (int. 22).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:23][CH2:22]1)=[O:6].[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C=O.CCOCC>[C:34]([N:4]([CH3:3])[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:25][CH2:26]1)=[O:6])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)N(C)C(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
0.1 g of sodium hydride (60% oil dispersion) is added to a solution of one g of N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide in 30 ml of dimethylformamide, and a solution of 0.19 g of acetyl chloride in 5 ml of ether is added thereto. After the mixture is stirred at 50° C. for 20 hours, the mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:n-hexane=4:1). 0.32 g of N-acetyl-N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].C1C(=O)N([Br:29])C(=O)C1.ClC1C=CC=CC=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][Br:29])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)/N=C/N(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 100 °C
Yield: 41 %

Procedure:
4′-Methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide (540.0 mg, 1786 μmol), NBS (318 mg, 1.8 mmol), and benzoyl peroxide (4.3 mg, 17.8 μmol) were dissolved in chlorobenzene (7.0 mL, 69 mmol) and the resulting solution was heated at 100° C. for 90 minutes. The mixture was cooled to room temperature and water was added. The mixture was extracted with DCM, washed with saturated NaHCO3 and saturated aqueous NaCl, extracted again with DCM, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (40 g, 0-100% EtOAc in hexanes), then taken up in EtOAc (4.5 mL) and DCM (1.5 mL). Additional DCM (3.0 mL) was added and the mixture was heated at 60° C. The mixture was cooled in the freezer overnight, then concentrated. The material was taken up in DCM (2 mL), EtOAc (6 mL) was added, and the resulting solution placed in the freezer. A precipitate formed and was filtered to yield the title compound (279 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][N:18]2[CH2:25][CH2:24][C:21]3([CH2:23][CH2:22]3)[C@H:20]([OH:26])[CH2:19]2)[CH2:14][O:13]C1(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:15]([CH2:14][OH:13])[CH2:16][CH2:17][N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[C@H:20]([OH:26])[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CCN2CCC3(CC3)[C@H](O)C2)N1C(=O)OCc1ccccc1
Solvent: CO
Solvent: O
Product: O=C(N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Yield: 95 %

Procedure:
A solution of (S)-4-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid benzyl ester (5.00 g, 12.9 mmol) in MeOH/water 9:1 (50 mL) was stirred at room temperature in the presence of Amberlite® IR-120 resin (15.8 g). After 16 h the resin was collected by filtration and washed with MeOH. The filtrate was discarded, and the product was recovered by digesting the Amberlite® resin three times in 7 M methanolic ammonia solution (60 mL) at room temperature over 15 min. The ammonia solutions were combined and evaporated to afford the title compound (4.27 g, 95%). Colourless oil, MS (ISP)=349.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:13][O:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:9]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[O:8][CH2:17][CH2:16][CH2:15][O:14][CH3:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(Br)cc1O
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COCCCOc1cc(Br)ccc1C(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2.60 g of 5-bromo-2-tert-butyl-phenol, 4.34 g of 3-methoxypropyl bromide and 5.55 g of caesium carbonate in 40 ml of acetone is stirred at 60° C. overnight. After cooling to room temperature, the mixture is filtered and the crude product obtained after concentration of the filtrate is purified by means of FC (80 g of silica gel, hexane/ethyl acetate=98:2). The title compound is obtained in the form of an oil: Rf (hexane/ethyl acetate=9:1)=0.56.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C@@H:19]12[CH2:25][C@@H:22]([CH:23]=[CH:24]1)[CH2:21][C@H:20]2[CH2:26][C:27](O)=[O:28]>>[C@@H:19]12[CH2:25][C@@H:22]([CH:23]=[CH:24]1)[CH2:21][C@H:20]2[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Reactant: Cc1ccsc1-c1nn(N)c(=O)c2ccccc12
Product: Cc1ccsc1-c1nn(NC(=O)C[C@@H]2C[C@@H]3C=C[C@H]2C3)c(=O)c2ccccc12

Procedure:
The product from Example 14B and 2-((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.38-8.40 (m, 1H), 7.89-8.05 (m, 2H), 7.72 (d, J=5.1 Hz, 1H), 7.62-7.65 (m, 1H), 7.12 (d, J=5.1 Hz, 1H), 6.22 (dd, J=5.7, 3.0 Hz, 1H), 6.06 (dd, J=5.7, 2.8 Hz, 1H), 2.88-2.90 (m, 1H), 2.77-2.79 (m, 1H), 2.42-2.52 (m, 1H), 2.10 (s, 3H), 2.08 (m, 2H), 1.90 (ddd, J=11.5, 9.1, 3.7 Hz, 1H), 1.33-1.36 (m, 1H), 1.26 (d, J=8.0 Hz, 1H), 0.60 (ddd, J=11.5, 4.3, 2.5 Hz, 1H); MS (APCI) M/Z 392 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH2:7][CH2:8][OH:9].CC(C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH2:7][C:8]([OH:15])=[O:9]
Reactant: Cc1cccc(OCCCO)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: Cc1cccc(OCCC(=O)O)c1

Procedure:
This compound was prepared in a manner analogous to that of Step C of Example 2, by the reaction of 2.0 grams (0.012 mole) of 3-(3-methylphenoxy)propan-1-ol and 10 mL of Jones Reagent in 30 mL of acetone. The yield of subject compound was 1.5 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1(/[CH:10]=[CH:11]/[C:12](=O)[CH3:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH3:13][C:12]1[CH2:11][CH:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:3][N:2]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC1=NNC(c2ccccc2)C1
Yield: 74.8 %

Procedure:
17.1 g (342 mmol) of hydrazine monohydrate was dissolved in 500 ml of methanol. Then, 50 g (342 mmol) of trans-4-phenyl-3-buten-2-one dissolved in 100 ml of methanol was gradually dropwise added thereto under stirring within a range of from 5° C. to 15° C. Then, the mixture was stirred at room temperature for 30 hours, and methanol was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 41.0 g of the desired 3-methyl-5-phenyl-2-pyrazoline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([N:12]2[CH2:16][C@H:15]([OH:17])[C@@H:14]([OH:18])[CH2:13]2)[N:3]=1.[NH3:19]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:19])=[O:9])[CH:5]=[C:4]([N:12]2[CH2:16][C@H:15]([OH:17])[C@@H:14]([OH:18])[CH2:13]2)[N:3]=1
Reactant: COC(=O)c1cc(N2C[C@H](O)[C@@H](O)C2)nc(Cl)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(N2C[C@H](O)[C@@H](O)C2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of methyl 2-chloro-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)pyrimidine-4-carboxylate (1.132 g, 4.14 mmol) in 7M ammonia in MeOH (12 mL) was allowed to sit at ambient temperature overnight. The reaction mixture was evaporated in vacuo and the residue was taken up in EtOAc (10 mL). The residue first dissolved then quickly precipitated a solid. After cooling back down to ambient temperature the precipitated solid was filtered off then dried under vacuum at 40° C. to give 2-chloro-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)pyrimidine-4-carboxamide as a tan powder (0.969 g, 3.75 mmol, 91% yield). LC/MS: m/z=259.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:9]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH:34]3[CH2:36][CH2:35]3)=[CH:26][CH:25]=2)[C:10]([S:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:11][N:12]=1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C1COCC1.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>[CH:34]1([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([N:9]3[C:8]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:12][N:11]=[C:10]3[S:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 90 °C
Yield: 73.7 %

Procedure:
Aqueous sodium carbonate solution (1M, 614 μL, 0.614 mmol) was added to a solution of tert-butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (60 mg, 0.123 mmol), phenylboronic acid (17 mg, 0.135 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol) in toluene (2 mL) and THF (1 mL). The mixture was bubbled under nitrogen for 5 mins and then heated to 90° C. under nitrogen for 20 hours. After cooling to room temp, water (20 mL) was added and the aqueous layer extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (40% EtOAc/hexanes) to give tert-butyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (44 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:32][CH3:33])=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([P:24](=[O:31])([O:28]CC)[O:25]CC)=[CH:20][CH:19]=3)[CH:15]=2)=[CH:4][N:3]=1.[OH-].[Na+:37]>C(O)C>[Na+:37].[Na+:37].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:32][CH3:33])=[C:14]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([P:24](=[O:25])([O-:28])[O-:31])=[CH:22][CH:23]=3)[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C#Cc2cc(Cc3cnc(N)nc3N)cc(OC)c2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2ccc(P(=O)([O-])[O-])cc2)c1OC
Yield: 29 %

Procedure:
16bc) 150 mg of diethyl [4-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-phenyl]-phosphonate (Example 12bo)) are dissolved in 5 ml of ethanol and treated with 5 ml of a 2N sodium hydroxide solution. The solution is held under reflux for 2 hrs., then cooled and chromatographed on MCl gel with water/acetonitrile. 43 mg of [4-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-phenyl]-phosphonic acid disodium salt are isolated. Yield: 29%. Mass spectrum: peaks inter alia at m/e: 463 (M++Na, 30%), 441 (M++H, 100%), 412 (22%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]3[C:14]([C:15]([O:17]CC)=O)=[N:13][N:12]([C:20]4[CH:28]=[CH:27][C:23]5[O:24][CH2:25][O:26][C:22]=5[CH:21]=4)[C:11]=3[C:4]=2[CH:3]=1.ClC1[N:38]=CC=CC=1C(Cl)=O.C(O)C(N)(CO)CO>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]3[C:14]([C:15]([NH2:38])=[O:17])=[N:13][N:12]([C:20]4[CH:28]=[CH:27][C:23]5[O:24][CH2:25][O:26][C:22]=5[CH:21]=4)[C:11]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1COc1ccc(N)cc1-2
Reactant: O=C(Cl)c1cccnc1Cl
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1COc1ccc(N)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.5 %

Procedure:
To a solution of title material from Example 28 (0.0791 g, 0.226 mmol) in dry pyridine (3 ml), 2-chloronicotinoyl chloride (0.0487 g, 0.2712 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with PS-trisamine (4.61 mmol/g, 0.2021 g, 0.9318 mmol) and stirred overnight. The resins were filtrated, washed with pyridine. The combined filtrate and washes were concentrated to dryness. The resulting residue was recrystallized with hot methanol, to give 8-amino-1-[1,3-benzodioxol-5-yl]-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (0.0922 g, 83.3%), which was characterized by 1H NMR, LC/MS (MH+ 489), and HPLC (96.6% purity).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH:1]1([C:4]([NH:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(N)CS
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarbonyl chloride (3.1 mL) was added to a suspension of triethylamine (4.68 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5.2 g) in DCM (200 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with ethanol and the solvent evaporated. The residue was suspend in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (2×150 mL), aqueous HCl solution (2M, 2×150 mL) and brine (150 mL), then dried over magnesium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to give the subtitled compound as a white solid. Yield 5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11].C([Mg]Cl)(C)C.[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>O1CCCC1.COC(C)(C)C>[Cl:10][C:4]1[C:5]([F:9])=[C:6]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1c(Cl)cc(I)c(F)c1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
1,3-Dichloro-2,4-difluoro-5-iodobenzene (4.0 g) was dissolved in tetrahydrofuran and cooled to −10 degree. A 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (10 ml) was added dropwise via a dropping funnel. The reaction mixture was stirred for 1 hour at same temperature. A solution of ethyl trifluoroacetate (2.76 g) in tetrahydrofuran (6 ml) was added dropwise and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with t-butyl methyl ether and washed with 1 N NaOH and then brine. The combined extracts were dried over magnesium sulfate. After filtered off, the filtrate was concentrated in vacuo to give crude product which was purified with Kugel-Rohr to give 1-(3,5-dichloro-2,4-difluorophenyl)-2,2,2-trifluoroethanone (2.5 g).