Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Oc2ccccc2)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-5-phenoxyphenol (0.38 g, 1.4 mmol) in 6 ml acetone was added K2CO3 (0.58 g, 4.2 mmol) and iodomethane (0.26 ml, 4.2 mmol). The-reaction mixture was heated to reflux for 8 h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH, water and brine. Drying over Na2SO4 afforded 0.36 g (92%) of 2-methoxy-4-phenoxybromobenzene.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>CCOCC.O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 1.0 M solution of 4-tolylmagnesium bromide in ether (20.5 ml) is added dropwise to a solution of diethyl oxalate (6.5 g) in anhydrous tetrahydrofuran (41 ml) under a nitrogen atmosphere and ice cooling. Five minutes after completing the addition, the mixture is stirred at room temperature for 1.5 hours. To the reaction mixture is added 1 N hydrochloric acid, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 2.99 g (76%) of ethyl 4-tolylglyoxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of (2-fluorophenyl)methanol (Aldrich, 10.0 g, 79.3 mmol) and triphenylphosphine (29.1 g, 111 mmol) in DCM was added CBr4 (31.6 g, 95.2 mmol) in small portions at 0° C. The mixture was stirred for 2 h at room temperature. The solvent was evaporated and the residue purified via flash chromatography (cyclohexanes:ethyl acetate 95:5) to give the title compound (14 g, 93%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.42 (t, 1H), 7.36-7.28 (m, 1H), 7.17-7.07 (m, 2H), 4.55 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[O-]CC.[Na+].[CH3:9][O:10][CH:11]([O:19][CH3:20])[C:12](=O)[CH:13]=[CH:14]N(C)C>C(O)C>[CH3:9][O:10][CH:11]([O:19][CH3:20])[C:12]1[CH:13]=[CH:14][N:4]=[C:2]([SH:3])[N:1]=1
Reactant: NC(N)=S
Reactant: COC(OC)C(=O)C=CN(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(OC)c1ccnc(S)n1
Temperature: 80 °C

Procedure:
A solution of thiourea (1.32 g, 17.3 mmol) and sodium ethoxide (21% wt in EtOH, 6.5 mL, 17.3 mmol) in ethanol (45 mL) was stirred at room temperature for 15 min, and then was added to a solution of 1,1-dimethoxy-4-dimethylaminobut-3-en-one (3.0 g, 17.3 mmol) in ethanol (20 mL). The reaction was heated to 80° C. for 16 h, and concentrated to dryness to yield 4-dimethoxymethyl-pyrimidine-2-thiol that was used crude in the methylation step. Methylation: To a solution of 4-dimethoxymethyl-pyrimidine-2-thol (4.3 g, 23.1 mmol) in DMF (55 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.4 g, 35.0 mmol). The reaction was stirred for 15 min at 0° C. and iodomethane (1.44 mL, 23.1 mmol) was added. After stirring for 16 h, the reaction was partitioned between ethyl acetate and water and extracted with ethyl acetate (2×). The combined organic extracts were dried with MgSO4, concentrated and purified by column chromatography (15% ethyl acetate/hexane) to yield pure acetal 46 (1.94g, 9.7 mmol, 42% for 2 steps). 1H NMR (chloroform-d1): δ=8.56 (d, 1H, J=5 Hz,), 7.19 (d, 1H, J=5 Hz,), 5.19 (s, 1H), 3.42 (s, 6H), 2.58 (s, 3H). Calculated mass=200.2, [M+H]+=201. HPLC (method C) rt=6.1 min (95.2% @ 210-370 nm).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:14][C@H:15]1[CH2:20][O:19][CH2:18][CH2:17][NH:16]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:16]2[CH2:17][CH2:18][O:19][CH2:20][C@@H:15]2[CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1COCCN1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reductive Amination Method B: 6-Bromopyridine-2-carbaldehyde (1.3 g, 7.0 mmol) was added to a 200 ml, round bottom under argon. Dichloroethane (28.0 ml) was added followed by (3S)-3-methylmorpholine (HCl salt) (1 g, 7.3 mmol) and triethylamine (1.0 ml, 7.3 mmol). The mixture was stirred for 0.5 hours at room temperature followed by the addition of sodium triacetoxyborohydride (2.07 g, 9.8 mmol) and the resulting slurry was maintained at room temperature overnight. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and was extracted once with DCM and once with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oily residue was purified via flash chromatography (silica, 0-10% methanol/ethyl acetate) to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][C:17](=[O:19])[CH2:18][CH:13]2[CH2:12]1.[CH2:20](O)[CH2:21][OH:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][C:17]3([CH2:18][CH:13]2[CH2:12]1)[O:22][CH2:21][CH2:20][O:19]3
Reactant: OCCO
Reactant: O=C1CC2CN(c3ccc([N+](=O)[O-])cc3F)CC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1

Procedure:
19.74 g (74.7 mmol) of 2-(2-fluoro-4-nitrophenyl)-5-oxo-hexahydro-cyclopenta[c]pyrrol prepared in the step 3 and 5.0 ml (89.6 mmol) of ethylene glycol were dissolved in 200 ml of benzene, 1.00 g (5.2 mmol) of p-toluene sulfonic acid hydrate was added, and the mixture was heated to reflux for 1 hour while removing generated water. After the reaction was completed, the mixture was washed with a saturated aqueous solution of sodium carbonate and water, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, of which NMR data is as follow.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][CH2:32][NH:33][CH3:34]>CN(C)C(=O)C>[OH:30][CH2:31][CH2:32][N:33]([CH3:34])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNCCO
Solvent: CC(=O)N(C)C
Product: CN(C/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with (2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 493 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]4[F:36])[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[O:29][C:20]1[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]2[N:24]=[C:16]([C:12]3[CH:11]=[C:10]([CH3:37])[C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[C:14]([CH3:15])[CH:13]=3)[O:17][C:18]=2[N:19]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 109.6 %

Procedure:
98 mg of {4-[5-(trans-2-fluoro-cyclohexyloxy)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid tert-butyl ester were dissolved in 3.5 ml of dichloromethane and treated with 1.5 ml of trifluoroacetic acid. After 16 h the mixture was concentrated and freeze-dried. 96 mg of the title compound were obtained.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[CH:26]=[N:25]1.O>CN(C)C=O>[O:33]([C:30]1[CH:31]=[C:32]2[C:27]([CH:26]=[N:25][NH:24]2)=[CH:28][CH:29]=1)[Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2cn[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Imidazole (3.0 g, manufactured by Kanto Chemical Co., Inc.) and t-butylchlorodiphenylsilane (12.1 g, manufactured by Tokyo Chemical Industry Co., Ltd.) were added to a solution of 1H-indazol-6-ol (3.0 g) synthesized according to the literature (L. F. Fieser, J. Am. Chem. Soc., 1926, 48, 1097-1107) in N,N-dimethylformamide (100 mL, manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred for 3 hours at room temperature. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether (3×200 mL), washed with brine (400 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to give 7.3 g of the title compound. LC-MS: HPLC retention time 2.05 minutes, m/z 373 (M+H), condition C-1.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([O:24][CH3:37])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (85.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9][CH2:8]1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]1([C:18]2[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C

Procedure:
A solution of 182 mg 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4- bromoanisole in 1 mL of tetrahydrofuran heated to 60° C. and 6 mg of Pd(PPh3)4 was added. To this mixture 0.5 mL of a 1M solution of phenylmagnesium bromide in tetrahydrofuran was added dropwise. The reaction mixture was heated at relux temperature under nitrogen for 1 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 4-phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]anisole which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded 140 mg of a solid which was treated with ethyl acetate-HCl to give 50 mg of 4-phenyl-2-[(4-(2-pyrimidinyl)piperazinyl)methyl]anisole dihydrochloride (Compound 1 ), mp 205°-207° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][O:14][C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)OCCOc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a mixture of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 3 described below) (500 mg), triethylamine (255 mg) and dry toluene (20 ml) was added dropwise an anhydrous toluene solution (1 ml) of ethyl isocyanate (179 mg). This mixture was then stirred at room temperature overnight, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 87 mg of ethylcarbamic acid 2-[4-(1-pyrazolyl)methylphenoxy]-ethyl ester (compound 37). Yield, 13%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: Cc1ccnc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (150 mg, 0.42 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (90 mg, 0.63 mmol) and 7-hydroxy-4-methylquinoline (71 mg, 0.46 mmol), (Chem. Berich. 1967, 100, 2077), in DMF (5.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The DMF solvent was removed by evaporation and the residue was taken up in 2N aqueous sodium hydroxide solution. The precipitate was filtered off, dried, taken up in dichloromethane and then filtered through phase separating paper. The solution was then evaporated to dryness. The resulting solid was recrystallised from acetonitrile, filtered and washed with diethyl ether to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4(4-methylquinolin-7-yloxy)quinazoline (84 mg, 42%).
Reaction SMILES: Cl[C:2]1C=C(C)C(C)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:25]Cl>>[Cl:19][C:12]1[C:11]2[O:10][C:3]([CH3:2])([CH3:4])[CH2:25][C:16]=2[C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=1
Reactant: ClCCl
Reactant: Cc1cc(Cl)c(Oc2cc(C)c(C)cc2Cl)cc1C
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(Cl)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 23.8 g of the methally 2-chloro-4,5-dimethylphenyl ether in 200 ml absolute dichloromethane at -70° C. was added 10 g of AlCl3 under a current of nitrogen gas. After stirring and warming to the room temperature over a period of 1 hour, the reaction mixture was added 200 ml of ice-water and the aqueous layer was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 20 g of 7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran as yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[Br:10][C:11]1[S:15][C:14]2[C:16](=[O:31])[CH:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:13]=2[CH:12]=1.[N-:32]=[N+]=[N-].[Na+]>>[Br:10][C:11]1[S:15][C:14]2[C:16](=[O:31])[NH:32][CH:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:13]=2[CH:12]=1
Reactant: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1NC(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 15 °C
Yield: 48.3 %

Procedure:
To a mixture of sulfuric acid (5.01 mL, 94.0 mmol) and chloroform (49.6 mL, 6.20E2 mmol) was added methyl 2-bromo-4-(3,4-dichlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (5.01 g, 11.9 mmol) followed by sodium azide (3.72 g, 57.2 mmol) in small portions over 3 h with vigorous stirring at 15° C. After addition, the mixture was stirred at rt overnight. The reaction was quenched by ice, basified with sodium bicarbonate, and extracted with DCM. The DCM layer was washed with brine, followed by sodium bicarbonate solution and brine. Dried and evaporated to afford crude product which was purified by silica gel chromatography to afford product as off-white solid (2.50 g, 48.2%). LCMS: (AA) ES+: 435, 437, 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.00 (dd, J=8.3, 2.2 Hz, 1H), 6.77 (s, 1H), 5.92 (t, J=9.3 Hz, 1H), 4.67 (d, J=3.3 Hz, 1H), 4.28 (t, J=3.6 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:36]([N:38]4[CH2:43][CH2:42][N:41]([C:44]5[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=5)[CH2:40][C@H:39]4[CH3:51])=[O:37])[CH:21]=3)[C:16]2=[O:52])=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:36]([N:38]4[CH2:43][CH2:42][N:41]([C:44]5[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=5)[CH2:40][C@H:39]4[CH3:51])=[O:37])[CH:21]=3)[C:16]2=[O:52])=[CH:11][CH:10]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2)CCN1C(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)OC(C)(C)C)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2)CCN1C(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred, room temperature mixture of (R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (58 mg, 0.094 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, the residue was purified via PTLC (Emerck 1 mm), eluted with CH2Cl2/MeOH=10:1 to give (R)-5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (46 mg, 0.082 mmol) as a light yellow solid. LCMS [M+H]+=560. 1H NMR (500 MHz, CDCl3) δ ppm: 8.43 (d, J=8.28 Hz, 1H), 7.56 (d, J=1.32 Hz, 1H), 7.44 (dd, J=8.28, 1.32 Hz, 1H), 7.26 (m, 2H), 7.25 (m, 2H), 6.96-7.07 (m, 2H), 6.86-6.93 (m, 2H), 6.48 (s, 1H), 3.52 (m, 3H), 2.96 (m, 1H), 2.79 (m, 1H), 2.31 (m, 4H), 1.55-1.68 (m, 6H), 1.50 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([Si:21]([O:24][CH2:25][CH2:26]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.O>[Si:21]([O:24][CH2:25][CH2:26][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (591 mg) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-Boc-4-hydroxypiperidine (32.2 g, 0.160 mol) in DCM (400 mL) were added triethylamine (26.8 mL, 0.192 mol), methanesulfonyl chloride (13.6 mL, 0.176 mol) and 4-dimethylaminopyridine (0.20 g, 0.0016 mol) at 0° C. undernitrogen atmosphere. The resulting mixture was slowly warmed to rt and stirred at rt overnight. The mixture was washed with sat. aq. NaHCO3 (3×80 mL), brine (2×80 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to give the title compound as a white solid. It was used in the next step without further purification. 1H NMR (CDCl3): δ=1.47 (s, 9H), 1.80-1.85 (m, 2H), 1.95-1.99 (m, 2H), 3.05 (s, 3H), 3.28-3.34 (m, 2H), 3.68-3.74 (m, 2H), 4.89 (mc, 1H).