Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:26](O)(=O)[CH:27]([CH3:29])[CH3:28].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[C:22]([O:21][C:19]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH2:2][NH:1][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:4][CH:5]=2)[CH:10]1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1CCCCC1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CNCc1ccc2c(c1)C(C1CCCCC1)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tert-butyl 7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (999 mg) was dissolved in methylene chloride. Isobutyric acid (0.33 mL), triethylamine (1.2 mL), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.32 g) were added thereto, followed by stirring at room temperature for 18 hours. Water was added to the mixture which was then extracted with chloroform. The extract was washed with a 1 M aqueous NaOH solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to obtain tert-butyl-1-cyclohexyl-7-[(isobutylamino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (468 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:12])[CH:3]=1.CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21].[Br-]>O1CCOCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])[CH:3]=1
Reactant: O=C(Br)CBr
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cc(F)c(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 4,5-difluoro-2-aminobenzoic acid (20.0 g, 115.5 mmol) in a mixture of anhydrous DMF (50 mL) and anhydrous dioxane (50 mL) was cooled to 0° C. under N2 using an ice-bath. Bromoacetyl bromide (23.3 g, 10.1 mL, 115.5 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 3/4 h period. After the addition of bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 200 mL of ice-water. The resulting precipitate was filtered, washed with water, and then dried in a vacuum desiccator overnight to afford 31.24 g (92%) of the title compound as a white solid, mp 177°-180° C.: 1H NMR (DMSO-d6) δ14.17 (bs, 1H), 11.66 (s, 1H), 8.47 (dd, J=13.6, J=7.6, 1H), 7.97 (dd, J=11.2, J=9.2, 1H), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ167.55, 165.45, 151.99 (dd, J=249, J=12.9), 144.53 (dd, J=242, J=12.9), 137.58 (dd, J=7.5, 1=3), 119.75 (d, J=18.9), 114.18 (t, J=3), 108.96 (d, J=23.5), 30.43; MS (EI m/z) 293 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: CCCOc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1O
Yield: 132.1 %

Procedure:
A mixture of 3-hydroxy-4-propoxybenzaldehyde (0.4 g, 2.1 mmol), 3,5-dimethoxyacetophenone (0.371 mg, 2.1 mmol) and 50% w/v of aqueous sodium hydroxide (3.3 ml, 0.206 mol) in methanol (10 ml) at room temperature for 18 h. The yellow solid that precipitated was filtered and sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.95 g (19%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 2H), 7.1 (d, 3H), 6.8 (d, 1H), 6.6 (d, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 3.9 (s, 6H), 1.9 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 160.9, 146.0, 144.9, 128.4, 122.6, 120.2, 112.9, 106.2, 104.9, 70.6, 55.6, 22.4, 10.4. Mass Spectrum m/e (M+1) 343. Anal. Calcd. for C20H22O5: C, 70.16; H, 6.48. Found C, 70.08; H, 6.38.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(-c2cc(O)no2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)c1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Yield: 76.3 %

Procedure:
3-Hydroxy-5-(4-isopropylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 77%) as a colorless powder.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:23](OC)=[O:24]>C(O)C>[O:24]=[C:23]1[C:14]2[N:15]=[N:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]=2[NH:2][N:1]1[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1nnc2ccccc2c1Cl
Solvent: CCO
Product: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
4-Hydrazinobenzoic acid (68.4 mg, 0.45 mmol) was mixed at room temperature with ethanol (5 ml) to give a creme-coloured suspension. Methyl 4-chlorocinnoline-3-carboxylate (100 mg, 0.45 mmol) was added and the mixture was heated to 45-50° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. Ethyl acetate (10 ml) was added to the residue. The mixture was stirred at room temperature for 1 h. The solids were collected by filtration and dried under vacuum. The title compound was isolated as a brown powder (120 mg, 0.39 mmol, 86%). LCMS: m/z 307 [M+H]+. NMR [DMSO-d6]: δ=7.69-7.77 (m, 1 Haryl); 7.81-7.90 (m, 2 Haryl); 8.05 (d, J=8.85, 2 Haryl); 8.20 (d, J=7.92 Hz, 1 Haryl); 8.33 (d, J=8.85 Hz, 2 Haryl); 14.64 (s, NH).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[O:14][CH2:13][CH2:12][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(C#N)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
A suspension of 3-acetylbenzonitrile (50.0 g), ethylene glycol (34.0 g) and boron trifluoride etherate (1 ml) in benzene (200 ml) was heated at 100° C. by means of a Dean-Stark apparatus for 5 hours. After cooling, a saturated aqueous sodium hydrogencarbonate solution (200 ml) was added. The benzene layer was collected and then dried with sodium sulfate. The solvent was removed under reduced pressure to afford 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.0 g) (oil).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:37])[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:8][C:9]=2[O:30][CH3:31])[O:4]1.[BH4-].[Na+]>C(O)C.O.C(OCC)C>[CH3:2][C:3]1([CH3:37])[CH2:12][CH:11]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH2:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:8][C:9]=2[O:30][CH3:31])[O:4]1
Reactant: CCCCCc1cc(OC)c2c(c1)OC(C)(C)CC2c1cc[n+](Cc2ccc3ccccc3c2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCCCCc1cc(OC)c2c(c1)OC(C)(C)CC2C1=CCN(Cc2ccc3ccccc3c2)CC1
Reaction time: 0.5 h

Procedure:
This pyridinium bromide (5.86g.) was dissolved in a mixture of ethanol (70 ml.) and water (23 ml.) and sodium borohydride (0.74g.) was added portionwise to the stirred solution at ambient temperature. At the end of the addition, the solution was stirred for a further 0.5 hours and was then diluted with diethyl ether (300 ml.) and water (300 ml.). The organic layer was separated, dried over anhydrous potassium carbonate and evaporated under reduced pressure. The residual amber gum (4.96g.) was purified via column chromatography on silica gel using 60°-80° petroleum ether/ethyl acetate mixtures as eluent to give 2,2-Dimethyl-5-methoxy-4-[1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl]-7-n-pentylchroman as an orange oil (2.70g.).
Reaction SMILES: [ClH:1].[CH2:2]1[CH2:7][CH2:6][C:5]2([CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)[CH2:4][CH2:3]1.[OH2:13]>>[ClH:1].[NH2:11][CH2:12][C:5]1([CH2:8][C:9]([OH:13])=[O:10])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CC2(CCCCC2)CN1
Reactant: O
Agent: Cl
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 108 °C
Yield: 60 %

Procedure:
22.3 1 of water and 22.3 1 of concentrated hydrochloric acid are mixed in a T100 reactor and 6.41 kg gabapentin lactam added thereto, while stirring. The clear brown solution formed is subsequently boiled under reflux for six hours at 108° C. and the reaction mixture is left to stand until it has cooled to 28° C.. The white precipitate obtained is again dissolved by the addition of a further 40 l of water. For the removal of still undissolved lactam, the reaction mixture is extracted three times with, in each case, 30 l dichloromethane. The pale yellow aqueous phase is evaporated to dryness in a vacuum evaporator (QVF 100 L), the temperature finally reaching to 80° C. at 133 Pa. The almost dry crystal mass is stirred in 12.8 l acetone and filtered off with suction. It is then washed with 2 l acetone and dried for four hours at 60° C. The yield is about 60% of theory.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:26]([OH:28])=O)[C:20]2=[O:29])=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:73]=[CH:72][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[N:52]([CH2:63][C:64]4[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=4)[N:53]=[C:54]([NH:55][CH:56]4[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]4)[C:47]=23)=[C:43]([F:74])[CH:42]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:71][O:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:52]2[C:48]3=[N:49][CH:50]=[CH:51][C:46]([O:45][C:44]4[CH:72]=[CH:73][C:41]([NH:40][C:26]([CH:21]5[CH2:22][CH2:23][CH2:24][CH2:25][N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[C:20]5=[O:29])=[O:28])=[CH:42][C:43]=4[F:74])=[C:47]3[C:54]([NH:55][CH:56]3[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]3)=[N:53]2)=[CH:69][CH:68]=1
Reactant: O=C(O)C1CCCCN(c2ccc(F)cc2)C1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)C5CCCCN(c6ccc(F)cc6)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
EDCI (48 mg, 0.25 mmol) was added to a mixture of the 1-(4-fluorophenyl)-2-oxoazepane-3-carboxylic acid (21 mg, 0.084 mmol) and HOBT (34 mg, 0.25 mmol) in DMF (0.5 mL) at ambient temperature, and the reaction mixture was stirred for 10 minutes at ambient temperature. 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (20 mg, 0.042 mmol, obtained from Example 101, Step A) and triethylamine (0.035 ml, 0.25 mmol) were added. The resulting mixture was stirred for 12 hours at ambient temperature. The reaction mixture was diluted with EtOAc. The organic layer washed with 10% aqueous LiCl, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (20 mg, 67% yield) as a white solid. LRMS (APCI pos) m/e 710.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.83 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (320 mg, 0.83 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.72 ml, 4.16 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (427 mg, 0.91 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.40 mmol, 49% yield) as a clear oil: LCMS (ES) m/e 571, 573 (M, M+2)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nocc1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a suspension of 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (4.0 g, 13.8 mmol) in THF (25 mL) was added a solution of lithium hydroxide monohydrate (1.2 g, 27.6 mmol) in water (25 mL) and then methanol (7 mL) added and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified to pH 1 with HCl (1 N, 80 mL) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (3.9 g, 100%) which was obtained as an off white solid. MS: m/e=277.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a mixture of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5 g, 13.65 mmol) in CH2Cl2 (20 mL) was added Dess-MartinPeriodinane (6.37 g, 15.02 mmol) and the reaction mixture was stirred at room temp for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with saturated NaHCO3 solution (100 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by a quick silica gel chromatography to afford (3.8 g, 76%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.10-7.98 (m, 1H), 7.89 (td, J=4.4, 1.5 Hz, 1H), 7.51-7.36 (m, 2H), 7.00 (s, 1H), 4.00 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[CH:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[O:25].CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:27]1[C:26]([CH:24]=[O:25])=[CH:30][N:29]=[CH:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: O=Cc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cncc1C=O
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2-(methanesulfonyloxy)ethyl}pyrrolidine (38.8 g) in N,N-dimethylformamide (380 ml) were added 4-formylimidazole (13.0 g) and potassium t-butoxide (15.2 g) and the mixture was stirred at 50°-60° C. for 2 hours. The reaction mixture was poured into water (600 ml) and extracted three times with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (750 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2-(5-formylimidazol-1-yl)ethyl}pyrrolidine (14.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][C:19]=3[CH:20]=2)=[O:13])=[CH:9][N:8]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[C:31]1([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([NH:11][C:12]([O:14][CH2:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:21][C:19]=4[CH:20]=3)=[O:13])=[CH:9][N:8]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1nc(-c2ccccc2)ncc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cnc(-c2ccccc2)nc1C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 5 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 2-phenyl-5-(5-phenyl-benzofuran-2-ylmethoxy-carbonylamino)-pyrimidine-4-carboxylic acid methyl ester (0.956. g, 1.99 mmol) in THF (20 mL), was added lithium hydroxide monohydrate (0.167 g, 3.99 mmol) in 4 ml of water. The mixture was stirred at 5° C. for 2 h, and 1N HCl was added to adjust the pH to 2. The solvents were removed in vacuo and the resulting suspension was filtered. Recrystallisation of the white crude solid gave 0.82 g of 2-phenyl-5-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-pyrimidine-4-carboxylic acid, mp: 184-185° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12](Cl)[N:11]=2)=[C:4]([CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(Cl)nc(C)c1[N+](=O)[O-]
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 4-(4-bromo-2,6-dimethylphenylthio)-2-chloro-6-methyl-5-nitropyrimidine (59 mmol), 4-aminobenzonitrile (65 mmol) and pyridine (59 mmol) in THF (300 ml) is heated to 80° C. for 10 hours. The reaction mixture is dissolved in methanol, washed with brine and extracted with ethyl acetate. The organic layer is washed twice with brine, dried over MgSO4 and concentrated to dryness. The solid is washed with a mixture of hexane:ethyl acetate (80:20) before filtration. After filtration, the solid is washed again with methanol. The filtrate may be concentrated and additional rounds of precipitation performed following the same procedure, until all product is recovered. The combined solids are recrystallized from acetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](=[CH2:24])[C:20]([F:23])([F:22])[F:21])=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([CH:19]([CH3:24])[C:20]([F:22])([F:21])[F:23])=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1
Reactant: C=C(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of N-(4-fluorophenyl)-1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-amine (0.067 g, 0.20 mmol) in 4 mL of THF/EtOH (3/1) was treated with palladium (10% wt. on activated carbon, 0.021 g, 0.020 mmol); and stirred at RT with a balloon of hydrogen. After 3 h, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give the crude product. The material was purified on an ISCO column (12 g, 50-75% EtOAc in hexanes) to afford the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: M+1=366.0.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:15]2[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([Br:17])=[CH:7][CH:8]=2)[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1.C(=O)=O.C(O)C.Cl.C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:18][CH3:19])[C:15]2[CH:14]=[C:13]([CH:28]=[O:29])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([Br:17])=[CH:7][CH:8]=2)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 9,9-diethyl-2,7-dibromofluorene (Example 2; 59.38 g, 0.1563 mol) in THF (325 mL) cooled in dry ice-ethanol bath, n-butyl lithium (104 mL of 1.6M solution in hexanes, 0.1664 mol, 1.06 eq.) was added dropwise over 25 minutes. After 20 minutes, DMF (17 mL, 0.22 mol) in THF (30 mL) was added, and the mixture was stirred in the cooling bath for 1.5 hours, and outside the bath for 1 hour. The reaction was then cooled to 5° C. and treated with hydrochloric acid (12.5 of concentrated hydrochloric acid diluted with 50 mL water). The mixture was diluted with 200 mL of toluene, and the aqueous phase was separated and extracted with 200 mL of toluene. The combined organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residual solids were recrystallized from heptane-ethyl acetate (9:1) mixture, to get colorless solids, 40.29 g (78.4% yield), m.p. 126-128° C. The mother liquor after chromatography over 150 g of silica gel, elution with 1:1 heptane-toluene mixture, and trituration of residual solids in hexanes gave additional product, 6.56 g (12.8% yield, total 91% yield), m.p. 126-128° C. Mass Spec: m/z 328, 330, (M+). A sample for analysis was prepared by recrystallization from hexanes, m.p. 127-129° C. Analysis: Calculated for C18H17BrO: C, 65.55%; H, 5.20%; Br, 24.27%. Found: C, 65.60%; H, 5.51%; Br, 24.71%.