Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.II.Br[C:10]1[S:11][C:12](Br)=[CH:13][CH:14]=1>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:10]1[S:11][C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: Brc1ccc(Br)s1
Reactant: Brc1cccs1
Agent: II
Solvent: C1CCOC1
Product: Brc1ccc(-c2cccs2)s1
Product: c1csc(-c2ccc(-c3cccs3)s2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16 %
Yield: 57 %

Procedure:
A solution of 2-bromothiophene (4.967 g, 24.92 mmol) in 5 ml dry THF was added dropwise to a mixture of Mg-turnings (752 mg, 30.94 mmol) and a small iodine crystal in 25 ml dry THF. After addition of about 1 ml of the bromothiophene solution, the reaction started and the mixture heated to reflux. The rest of the bromothiophene solution was added dropwise to the reaction, and the mixture was stirred for 1 hour at reflux. The reaction mixture was then transferred with a syringe into an addition funnel and was added slowly during 3 hours to an ice-cooled mixture of 2,5-dibromothiophene (8.206 g, 33.91 mmol) and PdCl2 (dppf)2 (250 mg, 0.306 mmol, complex with CH2Cl2 1:1) in 50 ml dry THF. This mixture was stirred for 2 hours at 0° C. and for 16 hours at room temperature. The solvent was evaporated in vacuo and the residue was suspended in EtOAc and washed with saturated NaHCO3 solution and brine. The aqueous layers were extracted with EtOAc and the organic layers were dried (MgSO4). Evaporation of the solvent and purification by FC (hexanes) gave 4.229 g 5-bromo-2,2′-bithiophene (6, FIG. 3) (17.25 mmol, 57%) and 1.216 g 2,2′:5′,2″-terthiophene (7, FIG. 3) (4.896 mmol, 16%) as yellow solids. 6:1H-NMR: 7.22 (dd, J=5.2, 0.8, 1 H), 7.11 (dd, J=3.6, 0.8, 1 H), 7.00 (dd, J=5.2, 3.6, 1 H), 6.96 (d, J=3.9, 1 H), 6.91 (d, J=3.9, 1 H). 13C-NMR: 138.9, 136.4 (2s), 130.6, 127.8, 124.8 (3d), 124.3 (s), 124.0, 123.8 (2d). EI-MS: 246 (100, [M]+, 81Br), 244 (88, [M]+, 79Br), 165 (39), 121 (53).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=1)([O-:35])=[O:34]>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:30])[NH:44][C@H:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)[CH3:43])=[CH:25][CH:26]=2
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].[H-].[Na+].[CH2:26](Br)[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([O:14][CH2:26][CH3:27])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCBr
Reactant: CCOC(=O)c1cc2cc(O)c(Cl)nc2n1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2n1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 1.0 g (2.93 mmol) 6-chloro-5-hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 20 mL N,N-dimethylformamide was added 0.14 g (3.23 mmol) sodium hydride (60% dispersion in mineral oil). After 30 min., 0.44 mL (0.64 g, 5.87 mmol) ethyl bromide was added and the suspension stirred for 1 h. The reaction mixture was poured into 10% aqueous citric acid solution and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to give the product as a colourless crystalline solid (93.4%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].BrP(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1cccc(C(C)=O)c1Br
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cccc(O)c1Br
Temperature: -40 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, 1-(2-bromo-3-methoxy phenyl)ethanone (30.5 g, 229 mmol) which had been obtained in Reference example 3 (3b) was dissolved in methylene chloride (500 mL), and added dropwise with a 1.0 M solution of tribromo phosphine in dichloromethane (293 mL, 293 mmol) at −80° C. over 5 hours. Upon the completion of the dropwise addition, the mixture was stirred for 17 hours at −40° C. Subsequently, the reaction solution was cooled to −80° C. and added dropwise with methanol (500 mL). Upon the completion of the dropwise addition, the temperature was raised to −40° C. followed by stirring for 3 hours. The temperature of the reaction solution was raised to room temperature. The solvent was distilled off under reduced pressure until the solution turned green. After adding ethanol, the mixture was extracted with ethyl acetate/hexane (1:1, V/V). After neutralization with a saturated aqueous solution of sodium hydrogen carbonate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 100:0-55:45, V/V) to give the title compound as a colorless oily substance (13.5 g, yield 47%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C@@H:9]1[CH2:11][O:10]1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[O:21]1[CH2:23][CH2:22]1.C[N:25](C)C=O>>[CH3:23][C:22]1[O:21][C:4]2[CH:14]=[CH:13][CH:12]=[C:6]([O:7][CH2:8][C@@H:9]3[CH2:11][O:10]3)[C:5]=2[N:25]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Reactant: C1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nc2c(OC[C@@H]3CO3)cccc2o1
Yield: 69.6 %

Procedure:
A suspension of 2-methyl-1.3-benzaxozol-4-ol (0.146 g, 0.98 mmol) (P. Crabbe, A. Villarino and J. M. Muchowski, J.Chem.Soc.Perk.I, 1973,2220-2222.), (2S)-2-[(3-nitrophenoxy)methyl]oxirane (0-192 g, 1.08 mmol) and cesium carbonate (0.478 g, 1.47 mmol) in dry dimethylformamide (DMF) (4 mL) was stirred at room temperature for 4 hours. More of the oxirane (0.04 g, 0.2 mmol) was added and the reaction continued for an additional hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed three times with water, dried and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane-ethyl acetate, 10:1) to afford the subtitle compound (0.14 g, 69.6%) as a colourless oil which solidified upon drying.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][F:35]>CS(C)=O.O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:34][F:35])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1nc(COCc2ccccc2)n(CF)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 1.5 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
In dimethylsulfoxide (20 ml)was dissolved 814 mg (2.0 mmol)of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropylimidazole (16a), with cooling to 0 to 3° C., followed by addition of 1.44 g (10.4 mmol)of potassium carbonate with stirring, and the mixture was stirred at the same temperature for 15 minutes. Then, 270 mg (2.40 mmol)of bromofluoromethane was added, and the mixture was stirred for 30 minutes at the same temperature and then for 3 hours at room temperature, and left overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the crude product was fractionated by silica gel column chromatography (ethyl acetate:methylene chloride=1:19). From the first fraction, 137 mg (yield 16%)of positional isomer (17x')of the target compound was obtained as oil. From the subsequent fraction, 700 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-fluoromethyl-4-isopropyl-1H-imidazole (17x)of the target compound was obtained as oil (yield 80%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:18]=3[CH:19]=2)=[C:11]([F:26])[N:10]=1)C)(C)(C)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:26][C:11]1[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:18]=3[CH:19]=2)=[CH:13][CH:14]=[C:9]([NH:7][CH3:6])[N:10]=1
Reactant: COc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3F)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2cc3cc(O)ccc3o2)c(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a stirred solution of [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester (66 mg, 0.184 mmol) in dichloromethane (30 mL) at 0° C. under nitrogen atmosphere, BBr3 (1M solution in CH2Cl2, 0.92 mL, 0.92 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and then cooled to 0° C. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted subsequently with 5% methanol in dichloromethane and with 5% methanol in ethyl acetate. The organic layers were washed with brine separately, dried over Na2SO4, filtered, concentrated and flash chromatographed using 30% ethyl acetate in hexane to give) 2-(2-fluoro-6-methylamino-pyridin-3-yl)-benzofuran-5-ol (19.9 mg) as a off white solid. 1H NMR (400 MHz, METHANOL-d4) δ: 8.02 (m, 1H), 7.27 (d, J=8.59 Hz, 1H), 6.90 (d, J=2.34 Hz, 1H), 6.77 (d, J=3.51 Hz, 1H), 6.70 (dd, J=8.59, 2.34 Hz, 1H), 6.43 (dd, J=8.59, 1.95 Hz, 1H), 2.89 (s, 3H). ESMS: m/z 259.47 [M+1]+
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1I
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1-c1ccc(F)cc1

Procedure:
By following a procedure analogous to Example 27 starting from the 4-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 21 and 4-fluorophenylboronic acid, 4-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=47%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:10]S(O)(=O)=O>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[N+:6]([O-:10])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1nccnc1Cl
Reactant: O=S(=O)(O)O
Product: N#Cc1c(Cl)ncc[n+]1[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
2-Chloro-3-cyanopyrazine (5.00 g, 35.94 mmol) was dissolved in 35 ml concentrated H2SO4 under nitrogen and cooled to 0° C. To this was added 11.65 g (43.95 mmol) K2S2O8 portionwise. The flask was fitted with a CaCl2 drying tube, the reaction mixture allowed to warm to rt and stir for 24 h. After partitioning between CHCl3 and ice water, the separated aqueous phase was extracted with CHCl3. The combined organics were washed with water, saturated NaHCO3, brine and dried over MgSO4. Concentration gave 2.01 g (36%) of the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, 1H), 8.38 (d, 1H). MS (DCI/NH3) m/e 173 (M+NH4)+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C:32]([CH3:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([C:32]([CH3:33])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:40])[CH:26]=1)[CH3:24]
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(C(C)(C)c2ccccc2)c1
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(C(C)(C)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-(1-methyl-1-phenyl-ethyl)-phenol as in Example 18 to afford 0.027 g (10%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C33H33O4F 512, found 513 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:37](OC(=O)C)(=[O:39])[CH3:38].[CH2:44]([O:46]CC)[CH3:45]>>[C:37]([O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:44](=[O:46])[CH3:45])=[O:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])(=[O:39])[CH3:38]
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2O)c1O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CCCc1c(OC(C)=O)ccc(C(=O)c2ccccc2OC(C)=O)c1O
Reaction time: 1 h

Procedure:
Five grams of (2,4-dihydroxy-3-propylphenyl)- (2-hydroxyphenyl)methanone, 5.63 ml of triethylamine, and approximately 50 mg of dimethylaminopyridine were dissolved in 50 ml of diethyl ether at 0° C. Acetic anhydride (3.8 ml) was added dropwise. After stirring for 1 hour, the reaction mixture was partitioned between diethyl ether and water. The organic layer was separated, washed with 1N hydrochloric acid, a saturated solution of sodium bicarbonate, and a saturated solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. Purification by high pressure liquid chromatography over silica gel eluting with a 10-25% ethyl acetate in hexane gradient and concentration of the appropriate fractions provided 2.6 g of the desired title product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1Br)[C:18]([OH:20])=[O:19])[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)[CH3:26]>>[CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=[CH:22][C:23]=1[C:32]1[CH:31]=[C:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:47])[CH:35]=[CH:34][C:33]=1[O:36][CH3:37])[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(C(=O)O)ccc1Br)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(=O)O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4-bromo-benzoic acid and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester. M+H is 506.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl (R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[C:32]1([Mg]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 1.88 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 6.6 ml. of 3M phenyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.90 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.88, 6.28, 6.47, 6.95, 7.25, 13.30, 14.35 μ. NMR: δ 3.93 (S, 4, ketal), 4.35 (M, 2, --CH2NO2), 5.15-6.05 (M, 4, olefinic --H), 5.88 (S, 2, --OH), 7.45 (M, 5, aromatic-HO ppm. Mass spectrum: M+ at m/e 515 (theory 515), M+ --H2O at m/e 497.2776 (theory 497.2776.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:41][CH:40]2[CH:35]([CH2:36][N:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:39]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:41][CH:40]5[CH:35]([CH2:36][N:37]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:39]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCN(C(=O)OC(C)(C)C)CC2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 37.4 %

Procedure:
A mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.70 g), K2CO3 (0.61 g) and tert-butyl 2-(3-chloropropyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (0.80 g) in 30 mL of DMF was stirred at 80° C. for 7 h, then poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as colorless oil (0.48 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 587.2 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.45 (s, 9H), 1.99-2.06 (m, 4H), 2.32-2.38 (m, 2H), 2.46-2.50 (m, 4H), 2.67-2.71 (m, 2H), 3.40-3.45 (m, 2H), 4.17-4.19 (m, 2H), 4.19 (s, 3H), 4.20-2.26 (m, 2H), 7.21 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.44 (s, 2H), 7.78 (t, J=4.4 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[C@@H:15]([NH2:17])[CH3:16])[CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[C@@H:15]([NH:17][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:16])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CCC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CCC1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
A mixture of (S)-1-(1-cyclobutyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (251 mg, 1.1 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (260 mg, 1.1 mmol) and DIPEA (1.0 mL, 5.5 mmol) in n-butanol (4 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 373 as a white solid (140 mg, 36%). LCMS (Method K): RT 2.93 min [M+H]+ 352.1 1H NMR (DMSO-d6, 400 MHz): δ 12.97 (1H, br), 8.33-7.76 (3H, m), 7.69-7.53 (2H, m), 7.09-6.98 (1H, m), 5.87 (1H, br s), 5.27-5.14 (1H, m), 2.93-2.72 (2H, m), 2.44 (1H, br s), 2.23 (1H, br s), 2.02-1.89 (1H, m), 1.82-1.61 (4H, m)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:11]1[C:10]([CH3:23])([CH3:24])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1Br)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1Br
Temperature: 70 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a stirred mixture solution of 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 3.8 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.3 g, 90%) as a light yellow solid: LC/MS m/e calcd for C18H18BrNO2 (M+H)+: 361.25, observed: 360.0 & 362.0.