Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:6]([CH3:20])[CH:5]=1.[Li+].[OH-]>C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:16]([O:15][C:13]([CH2:12][CH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[CH3:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(C)c(CCC(=O)OC(C)(C)C)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid methyl ester (10.8 g, 37.0 mmol) in ethanol (100 mL) a 2 M aq. solution of LiOH (50 mL) is added at 0° C. The turbid mixture is stirred at 0° C. for 30 min, then at rt for 4 h. The mixture is diluted with 10% aq. citric acid solution and extracted three times with diethyl ether. The combined organic extracts are dried over MgSO4, filtered and concentrated. The solid residue is suspended in diethyl ether/heptane, stirred at rt, and filtered. The slurry procedure in diethyl ether/heptane is repeated. The solid material is collected and dried under HV to give 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid (5.09 g) as a white crystalline powder; LC-MS: tR=0.95 min, [M+1]+=279.14; 1H NMR (CDCl3): δ 1.47 (s, 9 H), 2.30-2.40 (m, 2 H), 2.39 (s, 6 H), 2.94-3.03 (m, 2 H), 7.75 (s, 2 H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][OH:27])[CH:22]=[N:23][C:24]=1Cl>COCCOC.O.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>[Cl:18][C:19]1[C:24]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:23][CH:22]=[C:21]([CH2:26][OH:27])[CH:20]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ncc(CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
2.68 g of sodium carbonate (25.3 mmol), 1.15 g of 4-formylphenylboronic acid (7.66 mmol), and 0.27 g of Pd(PPh3)4 were added to 1.5 g of (5,6-dichloropyridin-3-yl)methanol (8.43 mmol) dissolved in 30 mL of 1,2-dimethoxyethane and 30 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated under about 50% reduced pressure to extract the aqueous layer with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 1.40 g of 4-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)benzaldehyde (yield 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16]>>[C:15]([NH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2sc3ccccc3c2c1
Product: CC(=O)Nc1ccc2sc3ccccc3c2c1

Procedure:
The title compound was prepared following the procedure of Example 2 using 2-aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133(6), 597-610) and acetyl chloride. NMR: 10.13 (brs, 1H), 8.6 (d, 1H), 8.15 (m, 1H), 8.0 (m, 1H), 7.9 (d, 1H), 7.6 (dd, 1H), 7.5 (m, 2H), 2.1 (s, 3H); m/z 242.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1Cl
Temperature: 105 °C

Procedure:
57 g (363.96 mmol) of 2-chloro-5-methylanisole is dissolved in 800 ml of carbon tetrachloride and mixed at room temperature with 69.9 g (393.08 mmol) of N-bromosuccinimide. After 174.6 mg of benzoyl peroxide is added, it is refluxed for five hours (bath temperature 105° C.). The reaction mixture is suctioned off via a glass fiber filter, rewashed, and the solution is spun in in a rotary evaporator. 83.6 g (97.5%) of the desired product (contains traces of starting material and dibromide), which is incorporated in crude form into the next stage, is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:16]=[C:15]3[C:17]([C:20](O)=[O:21])=[CH:18][NH:19][C:14]3=[N:13][CH:12]=2)=[N:3]1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:23]([NH:27][C:20]([C:17]1[C:15]2[C:14](=[N:13][CH:12]=[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[N:3]=3)[N:16]=2)[NH:19][CH:18]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccccc21
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccccc21
Yield: 32.9 %

Procedure:
2-(1-Methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (120 mg, 0.41 mmol), tert-butylamine (0.1 mL, 0.9 mmol) and HATU (233 mg, 0.61 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, 20 mL of 0.5N HCl were added to the residue, product extracted with ethyl acetate (3×50 mL), combined organics dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate/petroleum ether=2:1) to give N-tert-butyl-2-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (47 mg, 33.7%). LCMS: (M+H)+=349; 1H NMR (300 MHz, DMSO): δ 12.75 (s, 1H), 9.07 (s, 1H), 8.48 (d, 1H, J=7.8 Hz), 8.35 (s, 1H), 7.96 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.27-7.22 (m, 1H), 4.17 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1C(=O)O
Yield: 86.5 %

Procedure:
2-Amino-5-bromobenzoic acid (4.0 g, 0.018 mol) was dissolved in DMF (90 mL) and treated with carbonic acid di-tert-butyl ester (4.44 g, 0.020 mol), 4-dimethylamino-pyridine (0.219 g, 0.0018 mol) and triethylamine (2.8 mL, 0.020 mol) for 16 h at 70° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, then twice with 1 N hydrochloric acid, dried over sodium sulfate. The organic layers were concentrated to afford 5-bromo-2-tert-butoxycarbonylamino-benzoic acid as a yellow solid (4.92 g, 86.7%). 1H NMR (500 MHz, DMSO-d6) δ 1.46 (s, 9H), 7.72 (dd, J=2.5, J=8.5 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 10.44 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=O)=O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([SH:8])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
5-Chloro-2-methoxy-benzenesulfonyl chloride (1.0 g, 4.1 mmol) and triphenylphosphine (3.81 g, 14.5 mmol) were dissolved in THF (10 ml). Water (1.3 ml) was added and the mixture was stirred for 2 h at room temperature. The mixture was partitioned between 2N aqueous NaOH and diethylether. The aqueous phase was acidified to pH 1 with concentrated HCl and then extracted twice with methylene chloride. The combined organic layers were dried over MgSO4 and the solvent was evaporated to afford the desired product (690 mg), which was used in the next reaction step without further purification. MS m/z: 175 [M+H]+
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:19])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:28])C=1.O.[OH-].[Na+]>C(Cl)Cl>[C:13]1([C:9]2[C:8]3[CH:7]=[CH:6][C:5]4[O:19][CH:2]([CH2:3][OH:28])[CH2:1][C:4]=4[C:12]=3[O:11][N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCc1c(O)ccc2c(-c3ccccc3)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCC1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To an ice-cooled solution of 7-allyl-6-hydroxy-3-phenyl-1,2-benzisoxazole (17.5 g) in methylene chloride (500 ml), m-chloroperbenzoic acid (20.8 g) was added in small portions under agitation, and the mixture was refluxed for 4 hours. After cooling the mixture, water and an aqueous solution of 2N sodium hydroxide (80 ml) were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 18 g of 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 107°-109° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 267.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([NH:22][CH3:23])[N:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[N:36]=[C:37]=[O:38].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:37](=[O:38])[N:22]([C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[N:17]=[CH:18][N:19]=1)[CH3:23]
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Reactant: O=C=Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)ccc(C(F)(F)F)c4Cl)ncn3)cc2)CC1
Reaction time: 1.5 h

Procedure:
This oil is re-dissolved in 2 ml of toluene and added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (156 mg, 0.50 mmol; Example 145A) in 6 ml of toluene during 10 min. After 1.5 h, another 2 eq of 2,6-dichloro-3-trifluoromethyl-phenylisocyanate are added and stirring is continued for totally 2 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH/NH3aq, 95:5:0.5) gives the title compound: ESI-MS: 568/570 [MH]+; tR=4.1 min (gradient J); TLC: Rf=0.3 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:22][C:13]1[S:12][C:11]([CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:15][C:14]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(Cc1cc(-c2ccccc2)cs1)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(-c2ccccc2)c(Br)s1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
To a solution of tert-butyl methyl[(4-phenyl-2-thienyl)methyl]carbamate (4.77 g) in N,N-dimethylformamide (30 mL) was added N-bromosuccinimide (2.83 g) at room temperature and the mixture was stirred for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→19:1) to give the title compound as a pale-yellow oil (yield 4.1 g, yield of 2 steps 67%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]([NH:36][CH:37]([C:40](=[O:43])[CH2:41][CH3:42])[CH2:38][CH3:39])=O)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[O:43][C:40]([CH2:41][CH3:42])=[C:37]([CH2:38][CH3:39])[N:36]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C(=O)NC(CC)C(=O)CC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c(C)cc(-c3nc(CC)c(CC)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 170 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(1-propionyl-n-propyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and phosphorusoxychloride.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:30]1[C:35]([CH2:36][C:37](O)=[O:38])=[CH:34][CH:33]=[CH:32][N:31]=1>C(O)CCCC>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:14]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:35]3[CH2:36][C:37]2=[O:38])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)Cc1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCCCCO
Solvent: O
Product: O=C1Cc2cccnc2N1c1ccc(OCc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
A mixture of 4-(benzyloxy)aniline hydrochloride (2.21 g), 4-methylbenzenesulfonic acid hydrate (0.178 g), and (2-chloropyridin-3-yl)acetic acid (Journal of Medicinal Chemistry, 1990, 33, 2697-2706.) (1.61 g) in 1-pentanol (15 mL) was stirred at 140° C. for 24 h. After cooling to room temperature, the mixture was added to SiO2, and the mixture was concentrated and purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.39 g) as a pale yellow solid.
Reaction SMILES: Br.[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:32][C:33]([NH:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:5])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(CN)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CNC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 4.64 g of (±)-4-(2-amino-1-methylethyl)phenol hydrobromide, 100 ml of ethyl acetate, 6.92 g of potassium carbonate, 40 ml of water and 3.75 g of benzyloxycarbonyl chloride is stirred at room temperature overnight. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried, and then evaporated under reduced pressure to remove the solvent. 4.82 g of (±)-4-(2-benzyloxycarbonylamino-1-methylethyl)phenol are obtained as pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc(O)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 8.6 g (34.4 mmol) of 4-(1-ethoxyethoxy)-1-(4-hydroxyphenyl)-2-butyn-1-ol in 50 ml of methylene chloride was added dropwise ar 0° to a suspension of 89 g (1.02 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 15 minutes, filtered over magnesium sulphate and concentrated. Flash chromatography of the residue on 200 g of silica gel (elution agent ether/hexane 1:1) yielded 4-(1-ethoxyethoxy)-1-(4-hydroxyphenyl)-2-butyn-1 one as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](Cl)=[O:24]>O1CCCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][O:18]1)=[O:24]
Reactant: O=C(Cl)C1CCCO1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)C1CCCO1)C(C)C

Procedure:
617 g (3.68 mol) of (S)-valine methyl ester hydrochloride were suspended in about 2.2 l of tetrahydrofuran and 745 g (7.38 mol) of triethylamine were added. 451 g (3.35 mol) of tetrahydrofuran-2-carbonyl chloride in 200 ml of THF were added dropwise with stirring, the reaction temperature rising to about 65° C. After completion of the addition, the mixture was stirred at room temperature for a further 12 hours. The precipitate was filtered off with suction and thoroughly washed with tetrahydrofuran, and the combined organic phases were evaporated. The residue was dissolved in ether to remove excess (S)-valine methyl ester, shaken with water and dried in the customary manner. Vacuum distillation yields N-(2-tetrahydrofuroyl)-(S)-valine methyl ester (formula V with X=S, n=1, R=CH(CH3)2 and R'=CH3) as a colorless liquid, b.p. 98°-103° C./0.01 torr, yield: 611 g (80%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:10]>C(#N)C>[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[C:18]([Cl:1])[CH:19]=1)[CH3:10]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 50 °C
Yield: 80.6 %

Procedure:
N-Chlorosuccinimide (391 mg, 2.93 mmol) was added to a solution of (4-amino-phenyl)-acetic acid ethyl ester (500 mg, 2.79 mmol; [5438-70-0]) in acetonitrile (10 ml) under an argon atmosphere. The reaction mixture was heated to 50° C. for 1 h. The solvent was removed under reduced pressure and the residue taken up in iPrOAc/brine 1/1. The layers were separated and the aqueous layer was extracted with iPrOAc. The combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (481 mg, 2.25 mmol; 81%) as brown oil. MS: m/e=214.1 [M+H+].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[IH:11]>>[I:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Clc1ncnc2[nH]cnc12
Reactant: I
Product: Ic1ncnc2[nH]cnc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-chloro-9H-purine (684 mg, 4.46 mmol) and 6 mL of 57% hydriodic acid were stirred at 0° C. for 1.5 hours. The reaction yielded 840 mg of the product as a white powder. The solid was filtered off, suspended in 5 mL of water and brought to pH=8 with aqueous ammonia solution. The suspension was cooled down to 0° C. and the solid was filtered off, washed with cold water and dried to give the product.
Reaction SMILES: C(OC(N(CCCO[C:18]1[CH:19]=[C:20]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:21]=[CH:22][C:23]=1[CH2:24][NH:25][C:26]1[N:27]([C:37]2[N:38]=[CH:39][N:40]=[C:41]([NH2:44])[C:42]=2[N:43]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30])CC)=O)C1C=CC=CC=1.[CH3:51][OH:52]>[Pd]>[CH2:28]([NH:27][CH2:37][CH2:42][CH2:51][O:52][C:19]1[CH:18]=[C:23]([CH2:24][NH:25][C:26]2[N:27]([C:37]3[N:38]=[CH:39][N:40]=[C:41]([NH2:44])[C:42]=3[N:43]=2)[C@@H:28]2[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]2[OH:30])[CH:22]=[CH:21][C:20]=1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:29]
Reactant: CCN(CCCOc1cc(-c2ccccc2)ccc1CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: CCNCCCOc1cc(CNc2nc3c(N)ncnc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-{3-[3-(N-benzyloxycarbonyl-N-ethyl-amino)propoxy]biphenyl-4-ylmethylamino}adenosine (0.18 g) and 10% palladium on carbon (43.8 wt % H2O, 0.21 g) in methanol (5.3 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=8/1 to 6/1) to give the title compound (0.12 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:10]Cl>>[Cl:10][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1ccc(F)c(F)c1
Reactant: ClCl
Product: Cc1cc(F)c(F)cc1Cl

Procedure:
As shown in the above reaction, a mixture of 4-chloro-1-methyl-4,5,5-trifluorocyclohexene (IIIa) and 5-chloro-1-methyl-4,4,5-trifluorocyclohexene (IIIb) is prepared by reacting chlorotrifluoroethylene (CTFE) (I) and isoprene (II) at temperature range of 390 to 480° C. through continuous vapor phase condensation in a flow reactor and distilling the resultant. The mixture is dehydrohalogenated in the presence of alkali metal hydroxide and a phase transition catalyst to form 3,4-difluorotoluene (IV). The 3,4-difluorotoluene is reacted with chlorine gas in the presence of catalysts consisting of ferro-shaving and ferric chloride at temperature range of -10 to 40° C. without using any organic solvent to form 2-chloro-4,5-difluorotoluene (V). The 2-chloro-4,5-difluorotoluene is photo-reacted with chlorine gas under a lighting mercury lamp at temperature range of 80 to 140° C. without using any organic solvent to form 2-chloro-4,5-difluorobenzotrichloride (VI). The 2-chloro-4,5-difluorobenzotrichloride is reacted with aqueous acid solution at temperature range of 35 to 80° C. without using any organic solvent to give 2-chloro-4,5-difluorobenzoic acid (VII). The 2-chloro-4,5-difluorobenzoyl chloride (VIII) according to the present invention is prepared by reacting 2-chloro-4,5-difluorobenzotrichloride (VI) with zinc oxide.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]1=[O:32])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Product: O=C1c2ccccc2C(=O)N1CCOc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Yield: 48.6 %

Procedure:
In the same manner as in Synthesis Example 6, 500 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 382 mg of N-(2-hydroxyethyl)phthalimide were reacted to obtain 380 mg of 6-chloro-4-phenyl-2-(2-phthalimidoethoxy)quinazoline. Mp. 154.7° C. 1H NMR (CDCl3): 4.25 (2H, t, J=5.8 Hz), 4.84 (2H, t, J=5.8 Hz), 7.53-7.60 (3H, m), 7.67-7.71 (3H, m), 7.72-7.76 (3H, m), 7.78-7.82 (2H, m), 7.97 (1H, d, J=2.2 Hz).