Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[CH:21]=[O:22].NS(O)(=O)=[O:25].Cl[O-].[Na+]>O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([OH:25])=[O:22]
Reactant: COc1cccc(-c2ccc3c(C=O)c(OC)ccc3c2)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Reaction time: 0.5 h

Procedure:
200 mg of the compound 2-methoxy-6-(3-methoxyphenyl)-1-naphthaldehyde (0.68 mmol, 1 eq) is dissolved in a mixture of 8 ml of water and 17 ml of acetone. To the cooled reaction mixture, amidosulfonic acid (H2NSO3H) (1.51 mmol, 2.21 eq) and sodium hypochlorite (0.78 mmol, 1.14 eq) are added. After stirring for 30 min, the acetone is removed in vacuum on a rotary evaporator, and dichloromethane is added. The organic and aqueous phases are separated, and the organic phase is washed three times with saturated sodium chloride solution. After drying and concentrating the organic phase on a rotary evaporator, the desired product was obtained as a yellow solid in quantitative yield (209 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Product: Brc1cccc(OCc2ccccc2)c1
Yield: 97 %

Procedure:
Using the procedure described in Exampe 5, 3-bromophenol was reacted with benzyl bromide to give 3-benzyloxybromobenzene (97%), as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1.CO>C(OCC)(=O)C.C1CCCCC1>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:33][C:30]6[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=6)[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: O=Cc1ccncc1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CO
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(Cc4ccncc4)C3)ccc1OCC2

Procedure:
Following the procedure for 128, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with pyridine 4-carboxaldehyde, the crude product subjected flash chromatography (SiO2, gradient 0 to 20% MeOH in ethyl acetate) then trituration in cyclohexane to give 166 as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=5.20 Hz, 2H); 7.95 (s, 1H); 7.86 (d, J=2.20 Hz, 1H); 7.30-7.24 (m, 3H); 7.21-7.12 (m, 1H); 6.88-6.83 (m, 1H); 5.73-5.65 (m, 1H); 4.54 (t, J=5.99 Hz, 2H); 3.89-3.74 (m, 3H); 3.71 (s, 2H); 3.30 (s, 2H); 3.16 (t, J=5.99 Hz, 2 H); 1.58 (d, J=6.62 Hz, 6H). LCMS: RT=6.07 min, M+H+=442
Reaction SMILES: [CH2:1]=[CH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[CH2:10][C:11](=[O:12])[CH2:2][CH2:1]2
Reactant: C=C
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: -10 °C

Procedure:
To a two-liter round bottom flask equipped with a gas inlet tube connected to an external tank of ethylene, an addition funnel containing a solution of the crude 4-bromophenylacetyl chloride described above in methylene chloride (75 ml), a thermometer, a gas inlet adapter connected to a bubbler and a positive nitrogen flow, and a heavy-duty magnetic stirrer was added dry methylene chloride (1000 ml) and aluminium chloride (56 g, 0.42 mole). The stirred suspension was cooled to -10° C. using an ice/salt bath, and ethylene was introduced through the gas inlet tube, which was positioned just above the vortex. Dropwise addition of the phenylacetyl chloride solution was started at a moderate rate, and adjusted periodically so that the reaction temperature stayed below 0° C. Ethylene flow was continued for 30 minutes after addition of the acid chloride solution was complete, and then reaction mixture was poured over 2000 ml of ice, stirred vigorously for a few minutes, and left to sit until the ice melted. The methylene chloride layer was separated and the aqueous layer was extracted three times with methylene chloride (100 ml each). Combined methylene chloride layers were filtered through a short silica gel plug and then evaporated under reduced pressure to leave an amber-colored oil, which was purified using silica gel column chromatography, eluting with ethyl acetate:hexane (35:65) to give 6-bromo-2-tetralone as an amber crystalline solid. (25 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]1C=CC(S(O)=O)=[CH:21][C:17]=1C(O)=O.BrCC1CC1>C1(CO)CC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH:21]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: BrCC1CC1
Agent: OCC1CC1
Product: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and Bromomethyl-cyclopropane (+catalytic amount 12) in 20 ml cyclopropyl methanol/20 ml water and obtained in 8% yield. MS (m/e): 273.1 (MH−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[CH3:24][N:25]1[CH2:30]CN[CH2:27][CH2:26]1.ClCCCCCCO[C:39]1[C:40](OC)=[CH:41][CH:42]=[C:43]2[C:48]=1[NH:47][C:46](=O)[CH:45]=[C:44]2NC1C(Cl)=CN=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]3[CH2:48][CH2:24][N:25]([CH3:30])[CH2:26][CH2:27]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3), 1,8-dibromoocttane, and 1-methylpiperazine following the procedures outlined for Intermediate 4 (modifications: NMP used as solvent and 5.0 equiv of dibromide used) and Example 18, Step 2. 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 11.89 (br, 2H), 10.49 (s, 1H), 9.24 (s, 1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16 (d, 1H), 4.97 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.82-3.20 (br m, 8H), 3.10 (m, 2H), 2.81 (s, 3H), 1.84-1.66 (m, 4H), 1.46-1.26 (m, 8H); MS (ESI): 562.3.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>O1CCOCC1>[O:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1
Reactant: O=C1NOCC(=S)N1
Reactant: O=C1NCCN1
Solvent: C1COCCO1
Product: O=C1N=C(N2CCNC2=O)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.8 %

Procedure:
To a solution of 1.0 g (0.0075 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 50 ml of dry freshly distilled dioxane is added 0.66 g (0.007 mole) of 2-imidazolidone. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 1.3 g (94 percent) of 5-(2-oxo-1-imidazolidinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:13][CH2:12][CH:11]([OH:14])[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc(C(O)CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 6 h

Procedure:
(4-tert-butylphenyl)ethane 1,2 diol (0.5 g, 2.57 mmol) is dissolved in DMF in a 25 ml round bottom flask and to this were added imidazole (0.210 g, 3.09 mmol) and tert-butyldimethylsilyl chloride (0.46 g, 3.09 mmol). The mixture is stirred for 6 hours after which it is extracted in dichloromethane and the organic layer washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) affords the above mentioned product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:64][C:65]1[CH:66]=[C:67]2[C:71](=[CH:72][CH:73]=1)[CH2:70][CH2:69][CH2:68]2>C1(C)C=CC=CC=1>[CH2:70]1[C:71]2[C:67](=[CH:66][C:65]([NH:64][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:73][CH:72]=2)[CH2:68][CH2:69]1
Reactant: COC(=S)c1cc(Br)c(C)s1
Reactant: Nc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=S)c1cc(Nc2ccc3c(c2)CCC3)c(C)s1
Yield: 73.4 %

Procedure:
The same procedure as in Example 254, step (a) was followed using 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 74.8 mg (0.56 mmol) of 5-aminoindan in 900 μL of toluene, and chromatographed as before using 40% CH2Cl2-hexane to afford 100 mg (73%) of the title compound as a yellow resin. 1H-NMR (CDCl3, 400 MHz) δ2.05-2.12 (m, 2H), 2.85-2.90 (m, 4H), 3.86 (s, 3H), 6,09 (s, 1H), 6.82 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 7.14 (d, 1H, J=8.0 Hz), 7.70 (s, 1H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[O-]CC.[Na+].CN([CH:13]=[C:14]1[CH2:18][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C:15]1=O)C>C(O)C>[CH3:3][C:2]1[N:4]=[CH:13][C:14]2[CH2:18][NH:17][CH2:16][C:15]=2[N:5]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc2c(n1)CNC2
Temperature: 85 °C

Procedure:
A solution of acetamidine hydrochloride (12.8 g, 135 mmol) and sodium ethoxide (59 mL, 157.5 mmol) in anhydrous ethanol (400 mL) was stirred under nitrogen for 15 min, and 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one from Step B (17.2 g, 45 mmol) was added. The resulting mixture was heated at 85° C. for 3.5 h, quenched with a solution of 5% aqueous citric acid (50 mL), and evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution. There was some insoluble solid material between the aqueous and the organic layers, which was filtered thorough a Celite pad and washed with ethyl acetate. The combined aqueous layers were extracted twice with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by chromatography on a Biotage Horizon® system (silica gel, 10-75% ethyl acetate/dichloromethane gradient) to yield the N-trityl protected derivative of the desired product. A portion of this trityl protected product (1.9 g, 5.0 mmol) was dissolved in 4N methanolic hydrogen chloride (20 mL) and stirred at room temperature for 2.5 h. The solution was evaporated and the residue was purified by chromatography on a Biotage Horizon® system (silica, 4.5-14% gradient of 10% concentrated aqueous ammonium hydroxide in methanol/dichloromethane) to yield the desired product. LC-MS=136.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9](O)[CH2:10][OH:11].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cncc(C2OCCO2)c1
Yield: 88.8 %

Procedure:
3-Pyridinecarboxaldehyde (3.00 mL, 31.8 mmol), ethylene glycol (2.66 mL, 47.7 mmol) and p-toluenesulfonic acid (302 mg, 1.59 mmol) were suspended in toluene (100 mL). The mixture was heated to reflux under a nitrogen atmosphere for 2 hours, during which produced water was removed by use of a Dean-Stark trap. Then, a saturated aqueous potassium carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give 3-(1,3-dioxolan-2-yl)pyridine (4.27 g, yield: 89%).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:36][C:37]1[C:42]([CH:43]=O)=[CH:41][C:40]([I:45])=[CH:39][CH:38]=1>C(Cl)Cl.C1COCC1>[F:36][C:37]1[CH:38]=[CH:39][C:40]([I:45])=[CH:41][C:42]=1/[CH:43]=[CH:5]/[C:4]1[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:3]=1[CH3:2].[F:36][C:37]1[CH:38]=[CH:39][C:40]([I:45])=[CH:41][C:42]=1/[CH:43]=[CH:5]\[C:4]1[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:3]=1[CH3:2]
Reactant: Cc1cccc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(I)ccc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(C)c1/C=C/c1cc(I)ccc1F
Product: Cc1cccc(C)c1/C=C\c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-dimethylbenzyltriphenylphosphonium bromide (2.21 g, 4.8 mmol) in CH2Cl2 (30 mL) was added a solution of potassium tert-butoxide (5 mL of a 1 M solution in THF, 5 mmol) and the mixture was stirred at 0° C. for 15 min. The mixture was cooled to −78° C. and 6-fluoro-3-iodobenzaldehyde (1.0 g, 4.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between EtOAc and water and the combined organics were washed with 1 M HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (100% hexanes) gave (E)-2-(2-fluoro-5-iodostyryl)-1,3-dimethylbenzene (0.280 g) and (Z)-2-(2-fluoro-5-iodostyryl)-1,3-dimethylbenzene (0.472 g) with additional product collected as an E/Z mixture (0.450 g). Total yield (1.20 g, 85%). Trans-isomer: 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J=7.2, 2.4 Hz, 1H), 7.63 (dq, J=8.8, 2.4 Hz, 1H), 7.34 (d, J=16.8 Hz, 1H), 7.04-7.09 (m, 4H), 6.61 (d, J=16.8 Hz, 1H), 2.30 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
To a solution of methyl 4-(tertiarybutyloxy carbonylaminoethyl)-phenylacetate (0.500 g, 1.71 mmol) in a mixture of tetrahydrofuran (20 ml) and water (10 ml) was added aqueous lithium hydroxide (3.8 ml of a 0.50M solution, 1.90 mmol) and the resulting mixture was stirred at room temperature for 16 h. The organic solvent was removed under vacuum and the residue was diluted with water (40 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (1×30 ml), dried (MgSO4) and evaporated to give the pure title compound as colourless crystals (0.460 g), m.p. 94°-95° C. δ (360 MHz, CDCl3) 1.42 (9H, s, C(CH3)3), 2.77 (2H, br, m, ArCH2CH2NHBoc), 3.35 (2H, br, m, ArCH2CH2NHBoc), 3.61 (2H, s, ArCH2CO2H), 4.57 (1H, br, s, ArCH2CH 2 NHBoc), 7.14 (2H, d, J=7.7 Hz, ArH), 7.21 (2H, d, J=7.7 Hz, ArH); m/e (CI-) 278 (100%, m-H).
Reaction SMILES: [C:1]([N:5]1[CH:28]=[C:27]2[C:7]([CH:8]=[CH:9][C:10]3([CH2:26]2)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]3)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.CO.[O:39]1[CH2:43]CCC1>>[Br:29][CH:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:26][C:27]2[C:7](=[N:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:28]=2)[CH:8]1[O:39][CH3:43]
Reactant: CC(C)(C)n1cc2c(n1)C=CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COC1c2nn(C(C)(C)C)cc2CC2(CCN(C(=O)OCc3ccccc3)CC2)C1Br
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Benzyl 2-tert-butyl-2,4-dihydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (560 mg, 1.48 mmol) was dissolved in a 20% methanol/tetrahydrofuran mixture (25 mL). N-bromosuccinimide (315 mg, 1.77 mmol) was added and the mixture was stirred for 30 minutes. The mixture was concentrated under reduced pressure. The resultant oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by flash column chromatography (10-80% ethyl acetate/heptane) to yield 538 mg (73%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.27-7.43 (m, 6 H), 5.12 (s, 2 H), 4.74 (d, J=2.7 Hz, 1 H), 4.41 (d, J=2.5 Hz, 1 H), 3.60-3.84 (m, 2 H), 3.54-3.61 (m, 3 H), 3.14-3.39 (m, 2 H), 2.59 (s, 2 H), 1.86 (br. s., 1 H), 1.69 (br. s., 3 H), 1.51-1.60 (m, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16](F)=[O:17])=[N:9]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([NH:34][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[O:17])=[N:9]1
Reactant: Cc1cc(CCC(=O)F)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(CCC(=O)NS(=O)(=O)C(F)(F)F)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of acid fluoride 9 (0.14 g, 0.33 mmol) and DMAP 0.161 g (1.3 mmol) in dry DCM, trifluoromethanesulfonamide 0.147 g (0.98 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide 10 was purified on silica to yield 0.13 g as a white solid (72%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=1)#[N:16]
Reactant: Nc1cccc(O)c1
Reactant: N#Cc1cccc(Nc2nc(Cl)ncc2F)c1
Product: N#Cc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1
Yield: 62.2 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) as a white solid. The reaction of 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 3-aminophenol (66 mg, 0.6 mmol) gave N4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (acetone-d6): δ 6.48 (ddd, J=0.9, 2.4 and 7.8 Hz, 1 H), 7.10 (t, J=8.1 Hz, 1 H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1 H), 7.33 (t, J=2.1 Hz, 1 H), 7.45 (dt, J=1.2 and 7.8 Hz, 1 H), 7.54 (t, J=8.1 Hz, 1 H), 8.08 (d, J=3.3 Hz, 1 H), 8.14 (ddd, J=1.5, 2.7 and 8.4 Hz, 1 H), 8.39 (t, J=2.1 Hz, 1 H), 8.58 (s, 1 H, NH), 8.84 (s, 1 H, NH); 19F NMR (282 MHz, acetone-d6): δ −167.41; LCMS: ret. time: 17.75 min.; purity: 92.39%; MS (m/e): 322.59 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:32]([CH3:34])[CH3:33])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:45][C:43]=2C=1.CCN(CC)CC.CN>ClCCl>[CH:32]([N:8]([C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23](=[O:24])[NH:45][CH3:43])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:34])[CH3:33]
Reactant: On1nnc2ccccc21
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(C(=O)O)cn3c2)s1
Agent: CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CNC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
A solution of 6-(2-(tert-butoxycarbonyl(isopropyl)-amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.21 mmol) in dichloromethane was treated with EDC (48 mg, 0.25 mmol), HOBT (34 mg, 0.25 mmol), Et3N (25 mg. 0.25 mmol), methylamine (2 M in THF: 3 ml, 6 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue purified by chromatography on silica gel using ethyl acetate/hexanes (50%) as eluent to give 30 mg (30% yield) of tert-butyl isopropyl(5-(2-(methylcarbamoyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl)carbamate as a white solid. LCMS (Conditions C): 4.26 min (RT); (M+H)+=492.43 (100%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: NCCc1cccnc1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CNCCc4cccnc4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 66.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 3-(2-aminoethyl)pyridine (0.235 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-3-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone (80.5 mg, yield 66%).