Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[C:16]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:15][C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]#[CH:37]>O>[F:6][C:7]1[C:16]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:15][C:10]2[N:11]([CH2:37][C:36]#[CH:35])[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)sc3cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1c(=O)sc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To 10 ml of DMF, 0.4 g (1.2 mmol) of 3-(6-fluoro-benzothiazolin-2-on-5-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.18 g (1.3 mmol) of potassium carbonate and 0.15 g (1.3 mmol) of propargyl bromide were added, followed by heating and stirring at 70° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.32 g (yield: 72%) of the desired product. Melting point: 150-151° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Br:12][C:13]1[CH:14]=[C:15]([C:19]2([F:32])[C:24]([CH3:26])([CH3:25])[O:23][C:22](OCC)=[N:21][S:20]2(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2([F:32])[C:24]([CH3:25])([CH3:26])[O:23][C:22]([NH:1][C@H:2]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:4][OH:5])=[N:21][S:20]2(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC1=NS(=O)(=O)C(F)(c2cccc(Br)c2)C(C)(C)O1
Reactant: N[C@@H](CCO)c1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
In a round-bottom flask, 42 mg of 5-(3-bromophenyl)-2-ethoxy-5-fluoro-6,6-dimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide was dissolved under inert gas in 0.2 ml of dichloromethane and admixed with 20 mg of (S)-3-amino-3-phenylpropan-1-ol. After stirring at room temperature for 18 hours, the conversion was checked by LCMS. Since only traces of the product had formed, the reaction mixture was stirred at 100° C. for a further 4.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (13.1 mg) with a molecular weight of 485.4 g/mol (C20H22BrFN2O4S); MS (ESI): m/e=485 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[N:3]1.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:11][CH2:12][CH2:13][C:14]([C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:2]([CH3:1])[N:3]=1)=[O:15]
Reactant: Cn1ncc2c1CCCC2
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1nc(C(=O)CCCl)c2c1CCCC2
Temperature: 0 °C
Yield: 60.1 %

Procedure:
4,5,6,7-Tetrahydro-1-methyl-1H-indazole (10 g) and 3-chloropropionyl chloride (26 g) were dissolved in dichloroethane (100 ml) and aluminum chloride (28 g) was gradually added under an ice bath while stirring the mixture The reaction mixture was stirred for 17 hours at room temperature and poured into ice water. The reaction mixture was stirred for 2 hours at room temperature and extracted twice with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over magnesium sulfate. The magnesium sulfate was filtered off and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (silica gel 100 g) and 3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole (10 g) was obtained from an eluate of hexane:ethyl acetate=20:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH2:12].[C:14](Cl)(=[O:16])[CH3:15]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH:12][C:14](=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(CO)cc1N
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CO)cc1NC(C)=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 2-amino-4-hydroxymethyl-benzoic acid methyl ester (7.8 g, 43 mmol) in dioxane (150 mL) was added acetyl chloride (3.04 mL, 1 equiv) and the resulting mixture was stirred at 90° C. for 18 h. The solution was concentrated in vacuo and the resulting oil was sonicated in DCM/hexanes (2/8). The solid was filtered off, washed with hexanes and dried to afford a white solid (7.03 g, 73.2%) (ES-MS: m/z 224.2 [M+H]+, rt 3.75 min).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1F
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a stirred solution of crude 1-(bromomethyl)-2-fluoro-4-nitrobenzene (1.335 g, 5.705 mmol) in dimethylformamide was added potassium phthalimide (2.324 g, 12.55 mmol). The reaction mixture was stirred for 18 h The mixture was dissolved in ethyl acetate, washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give 2-(2-fluoro-4-nitrobenzyl)isoindoline-1,3-dione (1.229 g, 88%).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (119 mg, 94 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (122 mg, 99%) which was obtained as a white solid. MS: m/e=410.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1)=[N:5][CH:6]=[N:7]2.F[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)=[C:18]([CH3:23])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
A mixture of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol (0.47 g, 1.5 mmol), 2-fluoro-4-trifluoromethylpyridine (0.371 g, 2.25 mmol), and potassium carbonate (0.31 g, 2.25 mmol) in DMSO (7 mL) was heated at 90° C. overnight. The reaction was complete, as determined by LC-MS. After cooling to room temperature, water was added and the mixture was stirred for 10 min. The solid precipitate was collected by filtration, washed with water, and dried under vacuum at 50° C. to provide 0.533 g (77%) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as an off-white solid, M.P. 108-110° C. 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.31 (d, J=5.1 Hz, 1H), 7.34 (m, 1H), 7.13-7.21 (m, 4H), 6.96-7.03 (m, 2H), 6.71-6.84 (br, 1H), 3.94 (m, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.17 (s, 3H). LC/MS: 461.13 (M++1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C:11]3[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=3[C@@H:13]3[C@H:18]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16][CH2:15][N:14]3[C:8]=2[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[C:31]([N+:1]([O-:4])=[O:2])=[CH:30][C:9]2[O:10][C:11]3[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=3[C@@H:13]3[C@H:18]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16][CH2:15][N:14]3[C:8]=2[CH:7]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c([N+](=O)[O-])cc3Oc3ccccc3[C@H]12)C(F)(F)F
Yield: 93.5 %

Procedure:
Nitric acid (50 μL, 1.10 mmol) was added at 0° C. to a suspension of trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (210 mg, 0.53 mmol) in 4 mL of CH2Cl2. After stirring the mixture was extracted with ethyl acetate and the organic layer was washed with 5% aq. sodium bicarbonate, dried (Na2SO4) and evaporated to give trans-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (219 mg, 90%). Data: 1H-NMR (400 MHz, DMSO) 1.64-1.94 (m, 3H), 2.05 (br, 1H), 3.26 (t, J=8.0, 1H), 4.20 (d, J=8.0, 1H), 4.35 (d, J=8.0, 1H), 4.60 (dq, J=8.0, 3.0, 1H) 7.15 (m, 1H), 7.11-9.21 (6 ArH). (m/z)=443 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]2[O:7][C:8]([CH3:26])([CH3:25])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17](O)[CH2:18][Si](C)(C)C)=[CH:13][C:12]3=[O:24])[C:5]=2[CH:4]=1)#[N:2].[H-].[Na+].P([O-])([O-])([O-])=O>O1CCCC1>[C:1]([C:3]1[CH:28]=[CH:27][C:6]2[O:7][C:8]([CH3:25])([CH3:26])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][C:12]3=[O:24])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(C(O)C[Si](C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Yield: 73 %

Procedure:
In 22 ml of anhydrous tetrahydrofuran, is dissolved 875 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-2-trimethylsilylethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 26. Then, 89 mg of 60% oily sodium hydride is added to the solution at room temperature and reacted at room temperature for 4 hours. After stopping the reaction by adding 0.2 M phosphate buffer, the reaction mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/10 mixture of ethyl acetate/methylene chloride as a developing solvent. Thus, 493 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-vinyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CCN1CCN(S(N)(=O)=O)CC1

Procedure:
To a solution of 1-Ethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-Ethylpiperazine-1-sulfonamide as a white solid. A mixture of 4-ethylpiperazine-1-sulfonamide (0.289 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.50 g) in dioxane (10 mL) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([Na:10])[CH:9]=[CH:8][CH:7]=[CH:6]1)=[O:4].Cl[C:12]([O:14][CH3:15])=[O:13]>O1CCCC1>[CH3:15][O:14][C:12]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])([Na:10])[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: COC(=O)C1([Na])C=CC=C1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C1=CC=CC1([Na])C(=O)OC
Yield: 52 %

Procedure:
To a tetrahydrofuran solution of methoxycarbonyl cyclopentadienyl sodium (28 mmol/28 mol) preparated by the Rausch method, a tetrahydrofuran solution of methyl chloroformate (2g/30 ml) was added under cooling with ice. When the solution reached room temperature, it was filtered and concentrated under reduced pressure. Then, methylene chloride was added thereto to precipitate slightly pink precipitates. The precipitates were collected by filtration and dried to obtain 1.23 g of dimethoxycarbonylcyclopentadienyl sodium.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:39])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:38])[C:16]1[CH:21]=[C:20]([O:22]CC2C=CC=CC=2)[CH:19]=[CH:18][C:17]=1[O:30]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(CC(O)CNCCNC(=O)C1C=CC(OCC2C=CC=CC=2)=C(OCC2C=CC=CC=2)C=1)C1C=CC=CC=1>>[O:1]([CH2:8][CH:9]([OH:39])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:38])[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCNCC(O)COc1ccccc1)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: O=C(NCCNCC(O)COc1ccccc1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Product: O=C(NCCNCC(O)COc1ccccc1)c1cc(O)ccc1O

Procedure:
The process described in Example 12 is repeated except that 1-phenoxy-3-β-(2,5-dibenzyloxybenzamido)ethylamino-2-propanol (oxalate m.p. 176°-178° C.; prepared as described in Example 1 from β-(2,5-dibenzyloxybenzamido)ethylamine, m.p. 96°-98° C.) or 1-phenoxy-3-β-(3,4-dibenzyloxybenzamido)ethylamino-2-propanol (Example 6) is used as starting material. There are thus obtained respectively 1-phenoxy-3-β-(2,5-dihydroxybenzamido)ethylamino-2-propanol (hemioxalate m.p. 195°-197° C. after crystallisation from a mixture of ethanol and water), and 1-phenoxy-3-β-(3,4-dihydroxybenzamido)-ethylamino-2-propanol, m.p. 178°-180° C. after crystallisation from ethanol.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH4:10]>C(O)C>[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:1][OH:8])([OH:9])=[O:8]
Reactant: C
Reactant: CCCCC=CC(=O)O
Solvent: CCO
Product: O=C(O)CCCCCCc1ccccc1CO

Procedure:
A solution of 2.30 g. of the above heptenoic acid in 100 ml. of ethanol is stirred with 5 g. of activated charcoal for 30 minutes and filtered. The filtrate is hydrogenated at atmospheric pressure in the presence of 143 mg. of platinum oxide. The solution is filtered, evaporated and recrystallized from toluene to yield 2-(6-carboxyhexyl)benzyl alcohol as white crystals having a melting point of 75°-77° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[S:46](=[O:49])(=[O:48])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH:14]3[CH2:45][S:46](=[O:49])(=[O:48])[CH2:15]3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CC(Br)C1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(C3CS(=O)(=O)C3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-thietane 1,1-dioxide and isolated as white solid. MS (m/e): 387.3 (MH+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.Cl.Cl.[C:8]([C:12]1[CH:13]=[C:14]([NH2:28])[C:15]([NH2:27])=[C:16]([O:18][CH2:19][CH:20]([OH:26])[CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])[CH:17]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([OH:26])[CH2:21][NH:22][CH:23]([CH3:24])[CH3:25])[C:15]2[NH:27][C:1](=[O:2])[NH:28][C:14]=2[CH:13]=1)([CH3:10])([CH3:9])[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CC(C)NCC(O)COc1cc(C(C)(C)C)cc(N)c1N
Agent: Cl
Product: CC(C)NCC(O)COc1cc(C(C)(C)C)cc2[nH]c(=O)[nH]c12

Procedure:
Excess phosgene is passed at 20° to 25° C. into a solution of 5.5 g 5-tert.-butyl-2,3-diamino-1-[2-hydroxy-3-(2-propylamino)-propoxy]-benzene trihydrochloride in 50 ml. water, then thoroughly flushed with nitrogen, evaporated and the residue taken up in isopropanol. After a short time 2.3 g. (43% of theory) crystalline 6-tert.-butyl-4-[2-hydroxy-3-(2-propylamino)-propoxy]-2-benzimidazolinone hydrochloride precipitates out; decomposition point above 280° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([OH:19])[CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)C.[BH4-].[Na+].Cl>C(O)(C)C>[OH:19][CH:5]([CH2:4][OH:3])[CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2
Reactant: CCOC(=O)C(O)CCn1cnc2c(=O)[nH]c(N)nc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1nc2c(ncn2CCC(O)CO)c(=O)[nH]1

Procedure:
To a suspension of ethyl 4-(2-amino-1,6-dihydro-6-oxopurin-9-yl)-2-hydroxybutyrate (prepared according to Example 4) in iso-propanol was added an excess of sodium borohydride and the mixture was refluxed over night (at least 8 hours). Hydrochloric acid was added until a clear solution was obtained (neutral pH). After removal of the solvent the residue was dissolved in a minimum amount of boiling water and kept at 0° C. for a couple of hours. The solid was filtered off. The filtrate was evaporated at reduced pressure and the residue dissolved in hydrochloric acid (1 mol/l) and adsorbed on a cation exchange resin (Dowex 50 W, H+ -form). The resin was washed with water and then eluted with 5% ammonium hydroxide. The eluent was evaporated to give a crystalline solid which was recrystallized from water to afford colourless needles. M.p. 260°-1° C. (dec.) (uncorrected) UV spectra (hydrochloric acid 0.01 mol/l): λmax (nm) 277, 253 (ε=11500) M.S: 11.2 a J. (int): 239 (M+, 0.13), 222 (0.19), 221 (0.11), 152 (0.43), 151 (0.56), 44 (1.0).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Br[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[N:31][CH:32]=1>O1CCCC1>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:32][N:31]=1)[CH3:34]
Reactant: CCc1ccc(Br)cn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CC)nc1
Temperature: -78 °C

Procedure:
n-Butyllithium (2 ml, 1.6M in hexanes, 3.22 mmol) was added dropwise to an ice-cooled solution of diisopropylamine (0.45 ml, 3.22 mmol) in tetrahydrofuran (6 ml) under a nitrogen atmosphere, and the solution stirred for an hour. Tri-n-butyltin hydride (0.79 ml, 2.96 mmol) was added and the solution stirred for a further 2 hours, and then cooled to −78° C. A solution of 5-bromo-2-ethylpyridine (WO 97/01552) (500 mg, 2.69 mmol) in tetrahydrofuran (4 ml) was then added dropwise, and once addition was complete, the reaction was allowed to warm to room temperature, and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and aqueous ammonium chloride solution. The layers were separated, the organic phase dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to afford the tide compound, (210 mg, 19%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[N:7]([C:23]1[CH:28]=[C:27]([N:29]([CH3:53])[C:30]([N:32]([C:41]2[C:46]([Cl:47])=[C:45]([O:48][CH3:49])[CH:44]=[C:43]([O:50][CH3:51])[C:42]=2[Cl:52])[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:31])[N:26]=[CH:25][N:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:54])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][C:9]=1[NH2:20])[C:23]1[CH:28]=[C:27]([N:29]([CH3:53])[C:30]([N:32]([C:41]2[C:42]([Cl:52])=[C:43]([O:50][CH3:51])[CH:44]=[C:45]([O:48][CH3:49])[C:46]=2[Cl:47])[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])=[O:31])[N:26]=[CH:25][N:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: [Ni]
Solvent: CO
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3N)ncn2)c1Cl
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of {6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-(4-morpholin-4-yl-2-nitro-phenyl)-carbamic acid tert-butyl ester (crude, prepared above) in MeOH (20 mL) was added Raney-Ni (suspension in water) at room temperature, the resulting mixture was stirred for 2 hours under hydrogen atmosphere (1 atm). The reaction was filtered and concentrated. The residue was washed twice with MeOH to obtain title product (160 mg, yield: 70%). MS (ESI): 778 [M+H]+.