Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH:7]([OH:10])([CH3:9])[CH3:8]>>[Cl:1][CH:2]([Cl:6])[C:3]([O:10][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)O
Product: CC(C)OC(=O)C(Cl)Cl

Procedure:
9 g. (60 mMole) Dichloroacetyl chloride are added dropwise to 20 g. isopropanol cooled to 3° C. in an ice/water bath. The reaction solution is further stirred for 30 minutes at ambient temperature, whereafter excess alcohol is removed in a vacuum at ambient temperature. The residue is subsequently mixed with a mixture of ice water and dichloromethane. After separation of the phases, the organic phase is successively washed with water, aqueous sodium hydrogen carbonate solution and again with water and dried over anhydrous sodium sulphate. After removal of the solvent, there are obtained 7.5 g. (73% of theory) isopropyl dichloroacetate which, after distillation (67°-68° C., 24 hPa) is obtained as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:26]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CO
Reactant: COc1ccc(-c2oncc2CCC(=O)O)cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(OC)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionic acid (2.53 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionate (2.58 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 68–69° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[C:30]([C:37]([F:40])([F:39])[F:38])=[N:29]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([NH:10][S:33]([C:31]1[C:30]([C:37]([F:40])([F:38])[F:39])=[N:29][N:28]([CH3:27])[CH:32]=1)(=[O:35])=[O:34])[CH3:9]
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)c(F)c1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1-(3,5′-Difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 4′-bromo-2′-fluoroacetophenone to give 1-(4-bromo-2-fluoro-phenyl)-ethylamine. To a solution of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20.0 mg, 0.08 mmol) in dichloromethane (1 ml) was added triethylamine (8.1 mg, 0.08 mmol) and 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight then the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound (20 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.21-7.16 (m, 2H), 7.14-7.09 (m, 1H), 7.05-6.95 (m, 2H), 6.93-6.88 (m, 1H), 5.11 (d, 1H), 4.76 (dq, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 498.3 [M+Na]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=O)[C:17]3[N:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:20][C:21]=3[N:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=P(Cl)(Cl)[Cl:32]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:18]1[C:17]2[C:21](=[N:22][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][C:16]=2[Cl:32])[N:20]=[CH:19]1)[CH3:28]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1cnc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Product: CCOC(=O)Cn1cnc2nc(N3CCNCC3)nc(Cl)c21
Temperature: 80 °C

Procedure:
A mixture of 0.6 g of 4-(7-ethoxycarbonylmethyl-6-oxo-6,7-dihydro-1H-purin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, 4 in 20 mL of POCl3 was heated to 80° C. for 4 h. The excess POCl3 was removed by concentration in vacuo. The residue was poured into ice water. The pH was adjusted by 5N NaOH. The solution was extracted with methylene chloride. The organic phase was concentrated in vacuo to afford 5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][CH3:36])[CH2:30]1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:35]([CH:31]2[CH2:32][CH2:33][CH2:34][CH:29]([O:28][CH3:27])[CH2:30]2)[CH3:36])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: CNC1CCCC(OC)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCCC(N(C)c2cc(C)c(C(=O)NCc3cccc(F)c3)c(Cl)n2)C1
Temperature: 110 °C
Yield: 71.1 %

Procedure:
To a solution of 1.19 g (3.8 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2) in DMF (12 ml) were added 1.05 g (7.6 mmol) K2CO3 and 683 mg (3.8 mmol) 3-methoxy-N-methylcyclohexanamine and the reaction mixture was heated at 110° C. for 16 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 850 mg (2.7 mmol, 32%) 2-chloro-N-(3-fluorobenzyl)-6-((3-methoxycyclohexyl)(methyl)amino)-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])(C)(C)[CH3:3].N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:3]1([CH:2]=[NH+:6][O-:7])[C:12]2[C:11]([CH:12]=[CH:13][CH:9]=[CH:10][CH:11]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)NO
Reactant: c1ccncc1
Agent: Cl
Product: [O-][NH+]=Cc1ccc2cccccc1-2
Temperature: 95 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A carboxaldehyde group is converted readily to, for example, a N-tert-butyl nitrone group, by the following method: To a 0.2M solution of the aldehyde obtained by Procedure B in dry pyridine under argon at rt is added solid N-tert-butylhydroxylamine hydrochloride (1.5-2.0 eq). The mixture is heated with stirring to 95° C. for one hour and then allowed to cool to rt. The pyridine is removed on the rotary evaporator, and the residue is dissolved in CDCl3. The CDCl3 layer is washed with water and dried over MgSO4. Evaporation of the CDCl3 followed by silica gel chromatography of the residue (CDCl3:MeOH) provides the solid green azulenyl nitrone in 96% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]4[CH:26]=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:28]=[C:29]([F:31])[CH:30]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C2CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Product: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cc(F)cc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-2-yl)-cyclohexanone (as prepared in Example 22, Step C) and N-(azetidin-3-ylcarbamoylmethyl)-5-fluoro-3-trifluoromethyl-benzamide (analog synthesis by following the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B(O)O)[CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([C:39]2[CH2:43][CH2:42][CH2:41][CH:40]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: OB(O)C1=CCCC1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 29 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and cyclopent-1-ene-1-boronic acid gave 256 as an off-white solid (23 mg, 29% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.60 (s, 1H), 7.46 (s, 1H), 7.36 (s, 2H), 6.21 (t, J=2.4 Hz, 1H), 3.66 (s, 3H), 3.12-2.97 (m, 4H), 2.75 (t, J=7.3 Hz, 2H), 2.54 (s, 2H), 2.48 (d, J=5.9 Hz, 2H), 2.03-1.93 (m, 2H), 1.84-1.74 (m, 4H), 1.33-1.16 (m, 3H). LCMS (ES+) m/z 402 (M+1)
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]>CCOCC>[C:9]([N:13]=[N:14][C:15]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Solvent: CCOCC
Product: CC(C)(C)N=NC1(c2ccccc2)CCCCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a clean, dry 250 ml. round bottom 4 nech flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel, which was being purged with nitrogen, was added an ether solution containing 0.06 moles of phenylmagnesium bromide. The solution was cooled to 5° C. and a solution of 8.7 g. (0.043 moles) of 1-t-butylazo-1-chlorocyclohexane in 50 ml. of ether was added dropwise over 1/2 hour. After the addition was complete, the reaction was stirred for 15 minutes at room temperature and the excess phenylmagnesium bromide destroyed by the addition of wet ether. The reaction mixture was poured into 200 ml. of cold water and the ether layer separated, washed with 5% HCL, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the ether removed on a rotating evaporator leaving 9.75 g. (93%) of a yellow liquid. The infrared spectrum of the product was in agreement with the structure of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([O-])(=[O:28])C.[Na+]>C(O)(=O)C>[OH:28][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ccc(Cl)nn2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccc(O)nn2)CC1
Temperature: 100 °C

Procedure:
Benzyl 4-{[(6-chloro-3-pyridazinyl)amino]methyl}-1-piperidinecarboxylate (EXAMPLE 22) (37 mg, 0.10 mmol) was dissolved in acetic acid (5 mL) with sodium acetate (82 mg, 1.00 mmol) and was heated to 100° C. for 18 h. The volatiles were removed under reduced pressure and the residue partitioned between sat. NaHCO3 and ethyl acetate. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound as a clear oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1ccncc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccncc3)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-[4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (example 45) was reacted with pyridin-4-yl-boronic acid to give the title compound as light yellow oil. MS: 530.2 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[NH:9][C:10](=[O:17])[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]1.Br[CH2:25][C:26]([O:28]CC)=[O:27].O>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[N:9][C:10]([O:17][CH2:25][C:26]([OH:28])=[O:27])=[CH:11][C:12]([C:13]([F:14])([F:16])[F:15])=[C:7]2[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]1
Reactant: CCOC(=O)CBr
Reactant: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
NaH (23 mg, 0.56 mmol) was added to a stirred solution of 1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6(7H)-one (41 mg, 0.14 mmol) in DMF (4 ml) and the resulting mixture was stirred for 30 min. Then ethyl bromoacetate (47 mg, 6.50 mmol) was added and the mixture was stirred for additional 1 h. To the mixture water (0.5 ml) was added and stirred for 2 h. The reaction mixture was concentrated. 1N aqueous HCL was added to the mixture and the solution was extracted with diethyl ether. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (80% EtOAc in hexane) to yield the title compound (29 mg, 59%) [1H-NMR (CDCl3, 300 MHz) δ 7.45-7.30 (m, 5H), 7.05 (s, 1H), 7.00 (s, 1H), 5.03 (s, 2H), 3.81 (s, 3H); LCMS RtE=1.94 min; [M+H]+=351.0]
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][NH2:15].[CH:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[CH:16]([NH:15][CH2:14][CH:9]1[C:10]2[C:5](=[C:4]([O:3][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:17]
Reactant: COc1cccc2c1CCCC2CN
Reactant: CCOC=O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC2CNC=O

Procedure:
The product from Example 14 was converted to its free base (3.4 g) and dissolved into toluene (30 ml). Ethyl formate (5 ml) was added and the reaction stirred at reflux for 5 hr. The solvent was removed to afford a solid. Recrystallization from Et2O/CH2Cl2 afforded 3.07 g of desired product. Anal. calcd. for C13H17NO2 ; C, 71.21; H, 7.81; N, 6.39. Found: C, 71.26; H, 7.82; N, 6.41.
Reaction SMILES: [N+:1](=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]1=[O:14])=[N-:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(O)C>[Cl:15][S:16]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4](=[O:14])[C:3](=[N+:1]=[N-:2])[C:12]2=[O:13])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: [N-]=[N+]=C1C(=O)Oc2ccccc2C1=O
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)Oc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 50 °C
Yield: 81.2 %

Procedure:
A 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, water bath, nitrogen inlet and bubbler, thermometer and temperature controller was charged with 3-diazo-4-oxo-3,4-dihydrocoumarin (10.1 g, 53.7 mmol) prepared in accordance with Example 1 and chlorosulfonic acid (75.1 g). The reaction mixture was then heated to 50° C. and maintained at 50° C. for 42 hours, during which time HPLC analysis showed 99% conversion. The reaction was allowed to cool and was poured slowly, in portions, with stirring, into 420 g ice cold ethanol (the temperature of the ethanol slurry was kept below 10° C. throughout the addition). The ethanolic slurry was filtered, and dried in an oven overnight under vacuum at 58° C. to yield 12.5 g of pure 6-chlorosulfonyl-3-diazo-4-oxo-3,4-dihydrocoumarin (81% yield). The product was characterized by 13C NMR, DSC and UV-Vis. The results are as follows: the vacuum dried sample melted at 184.7° C. 13C-NMR in THF-d8 solvent, showed 9 singlet lines at the following chemical shifts, in ppm: 172.693, 1158.932, 157.050, 141.502, 134.467, 126.202, 121.104, 121.091, 77.983. The UV absorption spectrum of the product in THF solvent was determined at a dilution factor, DF=109,182.05 yielding, λ1 max=232 nm, ε1 max=29,532.1 liters/mole cm; and λ2max=288 nm, ε2 max=9,472.8 liters/mole cm.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=3)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: O=C(O)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1cccnc1
Yield: 50.6 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and nicotinic acid (40.6 mg, 0.33 mmol) as starting materials. The title compound (61 mg, 43.3%) was isolated as off white solid; MS (ESI): 366 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](N(OC)C)=[O:12])=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XX) (0.290 g, 0.78) in dry THF (5 mL) stirred at 0° C. under nitrogen was added lithium aluminum hydride (36 mg, 0.94 mmol). The solution was further stirred at 0° C. for 30 min. The reaction was quenched with a 0.4 N NaHSO4 solution (10 mL). The solution was extracted with DCM (3×15 mL). The combined organic layer was washed subsequently with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) as a viscous liquid (218 mg, 0.70 mmol, 91% yield). 1H NMR (CDCl3) δ ppm 1.52-1.74 (m, 2H), 1.95-2.18 (m, 2H), 2.37-2.49 (m, 2H) 3.87-3.98 (m, 1H), 3.99 (m, 1H), 6.18 (dd, J=10.20 Hz, J=2.39 Hz, 1H), 8.73 (d, J=3.01 Hz, 1H), 8.85 (d, J=3.01 Hz, 1H), 10.16 (s, 1H); ESIMS found for C12H12BrN3O2 m/z 310.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.CCN=C=NCCCN(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Nc1nc(-c2ccco2)c2ncn(CC(=O)O)c2n1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Nc1nc(-c2ccco2)c2ncn(CC(=O)Nc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
A solution of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DCM (2 mL) was treated with EDCI (96 mg, 0.5 mmol) and aniline (45 μL, 0.5 mmol), stirred at room temperature for 3 days, diluted with DCM, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; 1% MeOH in EtOAc) to give the title compound (51 mg, 31%) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([N+:1]([O-:4])=[O:2])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCc1cccs1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCCc1ccc([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 8 mL of acetic anhydride at −20° C. is added 1.2 mL of nitric acid (d=1.5). The mixture is kept at −20° C., and a solution of 4-thiophen-2-yl-butyric acid methyl ester (1.84 g, 10.0 mmol) in 12 mL of acetic anhydride is added dropwise. The reaction mixture is stirred for 10 minutes after completion of addition, and poured into an ice-water mixture. The product is extracted with ethyl acetate and the organic layer is washed with 10 N aqueous sodium hydroxide solution, dried and concentrated. The residue is purified by flash column chromatography eluting with 1:4 ethyl acetate:hexane to provide 1.32 g of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester as a yellow oil; 1H NMR (DMSO-d6) δ 1.93 (quintet, J=7 Hz, 2H), 2.41 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 3.59 (s, 3H), 7.04 (d, J=5 Hz, 1H), 8.01 (d, J=5 Hz, 1H); MS 229.0 (M)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCCCc1ccccn1
Reactant: BrCCCCCCBr
Product: BrCCCCCCOCCCCc1ccccn1

Procedure:
From 2-pyridinebutanol (3.96 g) and 1,6-dibromohexane (15 ml), with a reaction time of 4 h. FCC eluting with hexane→ether gave the title compound as a pale yellow oil (3.7 g), t.l.c. (hexane-diethyl ether 1:1) Rf 0.22.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:15]([O:22][CH3:23])[C:14]=2[CH3:24])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:25](OC(=O)C)(=O)[CH3:26]>>[CH3:23][O:22][C:15]1[C:14]([CH3:24])=[C:13]([C:11]([C:8]2[CH:9]=[CH:10][C:2]3[N:1]=[C:25]([CH3:26])[O:5][C:4](=[O:6])[C:3]=3[CH:7]=2)=[O:12])[N:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[CH:20]2
Reactant: COc1c(C)c(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Reactant: CC(=O)OC(C)=O
Product: COc1c(C)c(C(=O)c2ccc3nc(C)oc(=O)c3c2)n2ccccc12

Procedure:
0.100 g (0.31 mmol) of 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)-carbonyl]benzoic acid (Example 150 described in WO 03/084956) in 1 ml of acetic anhydride is refluxed for 3 hours. The reaction medium is concentrated under reduced pressure. 0.107 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][O:10][CH2:11]Cl)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][O:10][CH2:11][N:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]2=[O:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COC(=O)c1ccc(COCCl)cc1
Product: COC(=O)c1ccc(COCn2cc(Cl)cnc2=O)cc1
Yield: 62 %

Procedure:
was prepared as described in Example 3 from chloromethyl 4-methyloxycarbonylbenzyl ether (see Preparation 13) (8.8 mmol) and 5-chloropyrimidin-2-one (8.8 mmol) in 62% yield, m.p. 172° C. 1H NMR (CDCl3): δ3.92 (OMe), 4.77 (CH2Ph), 5.38 (CH2O), 7.2-8.2 (Ph), 7.78 asnd 8.50 (H-4, H-6, J 4 Hz).