Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10](=[O:20])[C:11]1[CH:16]=[C:15]([I:17])[C:14]([OH:18])=[C:13]([I:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].[OH-].[K+].Cl>O.C(#N)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10](=[O:20])[C:11]1[CH:12]=[C:13]([I:19])[C:14]([O:18][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:15]([I:17])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCCCC(=O)O)c(I)c1
Temperature: 25 °C

Procedure:
32.8 g (60 mmol) of 2-butyl-3-[3,5-diiodo-4-hydroxybenzoyl]benzofuran and 13.8 g (100 mmol) of anhydrous potassium carbonate are initially introduced into 200 ml of acetonitrile. 17.6 g (90 mmol) of ethyl 4-bromobutyrate are added dropwise at room temperature within the space of 30 minutes and the suspension is subsequently heated under reflux for 14 h. Once the reaction solution has been cooled down to room temperature, 200 ml of distilled water are added and the mixture is extracted 3 times with 100 ml of methyl tert-butyl ether. The combined organic extracts are dried and concentrated to dryness. The residue, which consists of 2-butyl-3-[3,5-diiodo-4-(3-ethoxycarbonyl-propyloxy)benzoyl]benzofuran, is introduced into 100 ml of isopropanol and a solution of 39.6 g (600 mmol) of 85% potassium hydroxide in 400 ml of distilled water is added. The suspension is heated at about 60° C. until a clear solution is formed. Once the solution has been cooled down to room temperature, 100 ml of 1N hydrochloric acid are added, and the mixture is adjusted to pH 3 with 32% hydrochloric acid while cooling, and then extracted 3 times with 200 ml of MTB ether on each occasion. The combined organic, dried, rotary-evaporated extracts are taken up in 50 ml of dichloromethane and left at 0° C. for several hours. The pale brown crystals which have precipitated out are stirred up with a further 50 ml of dichloromethane. After filtering with suction, washing and drying, 5.7 g (20%) of almost colourless crystals of 2-butyl-3-[3,5-diiodo-4-(3-carboxypropyloxy)-benzoyl]benzofuran are obtained which can, if desired, be further purified on a silica gel column (MTB ether/methanol=9:1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2ccc(CO)nc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccc(COS(C)(=O)=O)nc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the alcohol of Step 6 (303 mg, 1.68 mmol) in 17 mL of CH2Cl2 at -40° C., triethylamine (350 μl, 2.5 mmol) and methane-sulfonyl chloride (170 μl, 2.2 mmol) were added and the solution was stirred at -40° C. for 30 min and at 0° C. for 2 hr. Saturated aq. NaHCO3 was added and the product was extracted in CH2C12, dried over Na2SO4, concentrated, and the remaining water was stripped with toluene twice.
Reaction SMILES: S(Cl)(Cl)=O.C(Cl)Cl.[C:8]1([C:14]2[C:22]([CH:23]=[CH:24][C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[CH2:33][C:34]([OH:36])=O)=[O:26])=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH3:37]>CN(C)C=O>[C:8]1([C:14]2[C:22]([CH:23]=[CH:24][C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[CH2:33][C:34](=[O:36])[NH2:37])=[O:26])=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N
Reactant: O=C(O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.2 ml) was added dropwise to a solution of methylene chloride (dry, 40 ml) and N,N-dimethylformamide (0.2 ml) at 0° C. and stirred for 30 minutes. To this cooled solution was added (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(carboxymethyl)piperidine (trans isomer) (1.0 g) and the mixture was stirred for 1.5 hours. To this solution was added a solution of 28% aqueous ammonia solution (20 ml) and stirring was continued for further 2 hours. The aqueous and organic phases were separated and the organic layer was evaporated. The oily residue was subjected to column chromatography (silica gel, 60 mesh) using ethyl acetate as eluent. Evaporation of the solvent afforded (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(carbamoylmethyl)piperidine (trans isomer) (405 mg) as a white granular solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH:11]=[C:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(Cl)Cl.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O.CN(C=O)C>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:13]([C:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH:11]=2)=[O:15])=[CH:31][CH:30]=1
Reactant: O=C(O)C1=CCN(c2ncccn2)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)C1=CCN(c2ncccn2)CC1
Reaction time: 1.5 h

Procedure:
1-Pyrimidin-2-yl-1,2,3,6-tetrahydropyridine-4-carboxylic acid (55.0 mg, 0.27 mmol) and a catalytic amount of DMF were combined in CH2Cl2 (1.5 mL) and treated with (COCl)2 (0.033 mL, 0.38 mmol). The mixture was stirred for 90 minutes, diluted with toluene (0.5 mL), and concentrated to dryness under reduced pressure. The residue in CH2Cl2 (1.5 mL) was treated with pyridine (0.033 mL, 0.41 mmol), catalytic amount of DMAP, and 4-chloroaniline (41.0 mg, 0.32 mmol). The mixture was stirred for 1 hour, diluted with water, and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residure was purified by flash chromatography (15% ethyl acetate/CH2Cl2) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.35 (d, 2H), 7.51 (d, 2H), 7.39 (brs, 1H), 7.31 (d, 2H), 6.77 (sept, 1H), 6.54 (t, 1H), 4.43 (q, 2H), 4.03 (t, 2H), 2.58 (m, 2H); MS (m/z) 315.
Reaction SMILES: [CH2:1]([NH2:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(OCC)C>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][NH:12][C:30]([C:20]34[CH2:29][CH:24]5[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]5)[CH2:27]3)[CH2:21]4)=[O:31])=[CH:4][C:5]=2[O:6]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NCCc1ccc2c(c1)OCO2)C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
Dissolve 0.5 g. of homopiperonylamine in 5 ml. of ethyl ether and 2.5 ml. of triethylamine. The mixture is cooled in an ice-bath and a solution of 0.6 g. of 1-adamantane carboxylic acid chloride in 10 ml. of ethyl ether added dropwise. Stir the mixture for an additional 3 hours. Add water and extract the mixture with ethyl acetate. Wash the ethyl acetate extract with 2N hydrochloric acid, saturated sodium bicarbonate solution, and water. Dry over anhydrous sodium sulfate, filter and evaporate the filtrate to a residue. Crystallize the residue from ethyl acetate to obtain the product of this step, m.p. 146°-148°C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[N:4][CH:3]=1.[CH2:15]([O:22][CH2:23][C@H:24]([NH:28]C(OC(C)(C)C)=O)[C:25](O)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:28][C@@H:24]([CH2:23][O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][C:5]2[S:6][C:2]([Br:1])=[CH:3][N:4]=2)=[CH:9][CH:10]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ncc(Br)s2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ncc(Br)s2)cc1
Yield: 20 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(5-bromothiazol-2-yloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(5-bromothiazol-2-yloxy)phenyl)propanamide (200 mg, 20%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:24]I.[Cl-].[NH4+]>C(OCC)C.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([I:24])=[CH:11][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
A solution of 13.7 g of 5-[(tert-butoxycarbonyl)amino]-2-(isopropoxy)pyridine (54.3 mmol) and 18.1 mL of N,N,N′-tetramethylethylenediamine (120 mmol) in 200 mL of anhydrous diethyl ether was cooled to −78° C. and treated with n-BuLi (2.5 M in hexanes, 48 mL, 120 mmol) under an inert atmosphere. The mixture was placed in a −8° C. bath for 1 hour and allowed to slowly warm to room temperature. After 40 minutes, the flask was cooled to −8° C. and stirred for 4 hours. The mixture was then cooled to −78° C., treated with a solution of iodine (19.0 g, 75 mmol) in 100 mL of anhydrous THF, and the resulting mixture was stirred for 16 hours while allowing the bath to warm to 11° C. The reaction mixture was poured into a rapidly stirring aqueous saturated ammonium chloride solution (200 mL) and diluted with 100 mL of water and 300 mL of diethyl ether. The phases were separated and the aqueous layer was extracted with 200 mL of diethyl ether. The combined organic layers were washed with two 200 mL portions of sodium thiosulfate (10% aqueous solution), dried over sodium sulfate, decanted, and concentrated in vacuo. Chromatography on SiO2 (10% to 50% ethyl acetate in hexanes, gradient) gave the title product as an oil, which solidified on standing (13 g, 63% yield).
Reaction SMILES: [O-]CC.[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1.[N:24]([C:27]1[CH:36]=[C:35]2[C:30]([C:31]([CH3:38])=[CH:32][C:33](=[O:37])[O:34]2)=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C=O)C>[CH3:38][C:31]1[C:30]2[C:35](=[CH:36][C:27]([NH:24][C:25](=[O:26])[O:23][CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:6]4[O:5][C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[CH:7]=4)=[CH:17][CH:18]=3)=[CH:28][CH:29]=2)[O:34][C:33](=[O:37])[CH:32]=1
Reactant: Cc1cc(=O)oc2cc(N=C=O)ccc12
Reactant: OCc1ccc(OCc2cc3ccccc3o2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)oc2cc(NC(=O)OCc3ccc(OCc4cc5ccccc5o4)cc3)ccc12
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
Sodium ethoxide (40 mg, 0.59 mmol) was added to DMF at 0° C., and the suspension was stirred for 10 min. (4-(benzofuran-2-ylmethoxy)phenyl)methanol (150 mg, 0.59 mmol), was added and resulting mixture was stirred at this temperature for 0.5 h, then allowed to reach room temperature. To this mixture 76 (130 mg, 0.65 mmol) was added portionwise. Resulting mixture was stirred at room temperature for 2 h. DMF was evaporated off in-vacuo. The crude residue was purified by flash chromatography, eluting with hexane: EtOAc (2:1) to give the target compound (20 mg, 8%) as a white solid. m/z=456.10 (M+H). H1 NMR (500 MHz, DMSO-d6): δ=10.22 (1H, bs, NH), 7.69-7.64 (2H, m, ArH), 7.58 (1H, d, J=8.15 Hz, ArH), 7.55 (1H, s, ArH), 7.42 (2H, d, J=8.00 Hz, ArH), 7.33 (1H, t, J=7.70 Hz, ArH), 7.26 (1H, t, J=7.5 Hz, ArH), 7.11 (2H, d, J=8.28 Hz, ArH), 7.06 (1H, s, ArH), 6.23 (1H, s, ArH), 5.29 (2H, s, CH2), 5.12 (2H, s, CH2), 2.37 (3H, s, CH3).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[CH:16]4)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([O:32][CH:33]([CH3:35])[CH3:34])[CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:33]([O:32][C:30]1[CH:31]=[C:26]([NH:1][C:2]2[C:11]3[C:6](=[C:7]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[C:18]([NH:23][CH3:24])[N:17]=[CH:16]5)[C:8]([CH3:12])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:27]=[N:28][CH:29]=1)([CH3:35])[CH3:34]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(N)nccc34)ccc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cncc(OC(C)C)c5)nccc34)ccc2n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
To a solution 6-(1-amino-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (0.075 g, 0.24 mmol) in toluene (2.0 ml) charged to a 5-mL mircowave reaction vessel, 3-bromo-5-isopropoxypyridine (0.051 g, 0.24 mmol), X-Phos (0.0091 g, 0.019 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.0087 g, 0.0095 mmol), and sodium tert-butoxide (0.046 g, 0.48 mmol) were added and the reaction mixture heated to 160° C. The reaction mixture was stirred at 160° C. for 1 hrs. The reaction mixture was then diluted with EtOAc and partioned with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by HPLC to give 6-(1-(5-isopropoxypyridin-3-ylamino)-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine. MS (M+H)+ 451.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A quantity of 6.0 g of 3-chloro-2,4-difluorobenzoic acid is suspended in 20 ml of dichloromethane. A quantity of 2.99 ml of oxalyl chloride and 2 drops of DMF are then added. The suspension is stirred at room temperature overnight and the desired product is collected after evaporation of the solvent.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][NH:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][N:40]2[CH2:18][C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (122 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 520 mg) in DCE (10 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 85:15) to give (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid. TFA (3 mL) was added to a solution of (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; gradient from 100:0 to 85:15) to afford 395 as a white solid (153 mg, 63%). LCMS (Method G): RT=5.78 min, M+H+=474. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.26 (m, 2 H); 4.34 (m, 4 H); 4.00 (d, J=13.6 Hz, 1 H); 3.92-3.83 (m, 8 H); 3.70 (s, 1 H); 3.45 (s, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.25 (d, J=10.2 Hz, 1 H); 2.97-2.91 (m, 2 H); 2.70 (d, J=10.2 Hz, 1 H); 1.85 (d, J=10.1 Hz, 1 H); 1.70 (d, J=10.1 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:39]=2)/[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (190 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (250 mg, 2.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide (42 mg, 18%) as an amorphous white solid: EI-HRMS m/e calcd for C21H22N6O3S2 (M+) 458.1195, found 458.1192.
Reaction SMILES: [Br-].[C:2]([C:6]1[S:10][C:9](/[N:11]=C/N(C)C)=[N+:8]([CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]>Cl>[C:2]([C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCC[n+]1nc(C(C)(C)C)sc1/N=C/N(C)C
Agent: Cl
Agent: [Br-]
Product: CCCCn1nc(C(C)(C)C)sc1=N
Temperature: 25 °C

Procedure:
A solution of Example 162B (4 g, 11.45 mmol) in 1N HCl (12.6 mL) was heated at 65° C. for 12 hours. The mixture was cooled at room temperature and extracted with ether (2×20 mL). The aqueous phase was neutralized to pH 7 with concentrated ammonia and extracted with ether (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-80%) to give the title compound. LC/MS m/z 214 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCCOCn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 94.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (188 mg, 0.272 mmol) prepared in Example 159b, triethylsilane (0.20 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL), to yield the title compound (139 mg, 95%) as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][CH3:14])=[N:8][C:7]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][CH3:14])=[N:8][C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CCCNc1nc(N2CCNCC2)nc2c1S(=O)CC2
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CCCNc1nc(N2CCN(c3ccc(C#N)cc3)CC2)nc2c1S(=O)CC2
Yield: 52.8 %

Procedure:
Under an argon atmosphere 400 mg (5-oxo-2-piperazin-1-yl-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-propylamine (prepared in a similar manner to that described in Example 32), 245 mg 4-bromobenzonitrile, 321 mg palladium(II)acetate, 120 mg Xantphos and 620 mg caesium carbonate are stirred in 2.50 ml degassed toluene for 5 hours at 80° C. After cooling the reaction mixture is extracted with ethyl acetate and saturated sodium chloride solution. The organic phase is dried and evaporated to dryness. The residue is purified by preparative HPLC (method A). 282 mg of the product are obtained as a powder. Analytical HPLC-MS (method A): RT=2.37 min The two enantiomers may be separated by chiral HPLC (column: Diacel OD-H, 250×4.6 mm, 5 μm, eluant: (hexane+cyclohexylamine (0.2%))/EtOH (65/35), flow rate: 1 ml/min): enantiomer 1: RT=7.9 min (Example 148); enantiomer 2: RT=9.6 min.