Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.FC(F)(F)[C:14](O)=[O:15].C1N2CN3CN(C2)CN1C3.C1(C)C=CC=CC=1.CO>C(OCC)(=O)C.O>[CH:14]([C:7]1[CH:6]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:4]=[CH:3][C:2]=1[OH:1])=[O:15]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1ccc(O)c(C=O)c1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
25 g of N-(4-hydroxyphenyl)acetamide (0.165 mol; 1 equivalent) and 92.7 g of trifluoroacetic acid (0.661 mol; 4 equivalents) are placed in a 500 ml reactor. The mixture is stirred, and 92.7 g of hexamethylenetetramine (0.661 mol; 4 equivalents) are then added portionwise. The reaction is exothermic. A temperature of 70° C. is maintained over 18 hours, while monitoring the reaction progress by thin-layer chromatography (eluent: 8/2 toluene/methanol). The reaction medium is allowed to warm to room temperature. It becomes thick, and is diluted by addition of 200 ml of water to facilitate the stirring. 100 ml of ethyl acetate are then added. Stirring is continued and the phases are allowed to separate by settling. 300 ml of water and 200 ml of ethyl acetate are added, the mixture is stirred and the phases are then allowed to separate by settling. The aqueous phase is removed first, then the organic phase. The organic phase is then washed twice with 150 ml of water in total to collect, after phase separation, a new organic phase and a new aqueous phase. This new organic phase is then concentrated on a rotary evaporator (T=45° C.; 50 mmHg). 14 g of the desired compound are thus obtained in the form of crystals recovered from an orange-red solution.
Reaction SMILES: CCCCCC.[CH3:7][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([OH:16])[CH:15]=1)=[O:9].C(OCC)(=[O:19])C>>[OH:16][C:14]1[CH:15]=[C:10]([C:8]([CH:7]=[O:19])=[O:9])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccc(O)c1
Solvent: CCCCCC
Product: O=CC(=O)c1cccc(O)c1

Procedure:
Using 1:1 hexane:ethyl acetate as eluant, the method of Preparation 68 was employed to convert 3-hydroxyacetophenone (15.0 g., 0.11 mol) to present title product, 7.4 g.; 1H-nmr (DMSO-d6) 7.09 (m, 2H), 7.43 (m, 3H), 9.75 (br m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[S:14][C:13](=[S:15])[NH:12][C:11]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[S:14][C:13](=[S:15])[N:12]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=S)SC1=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1C(=Cc2ccc(Cl)c(Cl)c2)SC(=S)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
5-(3,4-dichlorophenylmethylene)-4-oxo-2-thionothiazolidine (100 mg, 0.345 mmol, 1.0equiv) was suspended in 653 μL of anhydrous pyridine, followed by the addition of 44 μL benzoyl chloride (0.379 mmol, 1.1 equiv). After about 2 minutes a yellow precipitate formed. The reaction was stirred at rt for 30 minutes. The pyridine was evaporated and the residue was purified by column chromatography (SiO2, EtOAc/hexanes) to yield 62 mg of 5-(3,4-dichlorophenylmethylene)-3-(benzoyl)-4-oxo-2-thionothiazolidine (0.157 mmol, 46%) as a yellow solid. Anal. calcd for C17H9Cl2NO2S2: C, 51.78; H, 2.30; N, 3.55; S, 16.26. Found: C, 52.04; H, 2.47; N, 3.48; S, 16.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24][OH:25])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:25][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1)(=[O:44])=[O:43]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) in dry CH2Cl2 (2 mL) was added Et3N (33 mg, 0.33 mmol) at 0˜−5° C. Then a solution of MsCl (12 mg, 0.13 mmol) in dry CH2Cl2 (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. When the reaction was over, water (10 mL) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers was washed with 10% citric acid, aqueous NaHCO3 and brine respectively, dried over Na2SO4, filtered and concentrated to give 2-((S)-3-((S)-1-(2′,4′-difluorobi-phenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (58 mg, crude), which was used for the next step without purification.
Reaction SMILES: C[C:2]1OC(=O)[C:5]2[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:6]=2[N:7]=1.N1C2C(=CC=CC=2)[C:19](=[O:26])NC=1.CC1NC(=O)C2C(=CC=C([N+]([O-])=O)C=2)N=1.N.ClC1C2C(=CC=CC=2)N=CN=1.[Cl:54][C:55]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([N+:65]([O-:67])=[O:66])[CH:63]=2)[N:58]=[C:57]([CH3:68])[N:56]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:54][C:55]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([N+:65]([O-:67])=[O:66])[CH:63]=2)[N:58]=[C:57]([CH3:68])[N:56]=1.[CH3:2][NH:7][C:6]1[CH:5]=[CH:11][C:10]([O:26][CH3:19])=[CH:9][CH:8]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Agent: Cc1nc2ccc([N+](=O)[O-])cc2c(=O)[nH]1
Agent: Clc1ncnc2ccccc12
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1ccc(OC)cc1

Procedure:
Compounds of this invention with Formula I-VIb, wherein R2 is an alkyl group, could be prepared as illustrated by the exemplary reaction in Scheme 9. Reaction of a substituted 2-amino-benzoic acid, such as 2-amino-5-nitro-benzoic acid, with acetic anhydride, produces the corresponding substituted 2-methyl-4H-benzo[d][1,3]oxazine-4-one, such as 2-methyl-6-nitro-4H-benzo[d][1,3]oxazine-4-one, which is converted to the corresponding quinazoline-4(3H)-one, such as 2-methyl-6-nitro-quinazoline-4(3H)-one, by treatment with ammonia in dioxane. The compound is then converted to the corresponding 4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline by reaction with phosphorylchloride. Reaction of the 4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline with a substituted arylamine or heteroarylamine, such as N-methyl-4-methoxy-aniline, produces the corresponding 4-(arylamino or heteroarylamino)-quinazoline, such as substituted 2-methyl-6-nitro-4-anilino-quinazoline. Other substituted 2-amino-benzoic acid that can be used for the reaction include 2-amino-4-nitro-benzoic acid, 2-amino-5-chloro-benzoic acid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:17][C:18]([CH3:20])=O>>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][CH2:4][CH2:3][N:5]3[CH:6]([CH3:15])[CH2:7][CH2:17][CH:18]3[CH3:20])=[CH:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Agent: Cl
Product: CC1CCC(C)N1CCNc1ccnc2cc(Cl)ccc12

Procedure:
0.35 g (isomer mixture cis:trans=15:1) from 1.3 g of N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride; yellowish crystals from acetone, m.p.: 127°-130° C.
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]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[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:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]2>CC(N(C)C)=O>[C:40]([C:35]1[NH:36][C:37]2[C:33]([CH:34]=1)=[CH:32][C:31]([O:30][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:39][CH:38]=2)([OH:42])=[O:41]
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C(=O)O)cc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (345 mg, 5.0 mmol), 5-hydroxy-2-indolecarboxylic acid (106 mg, 0.6 mmol) and DMA (2.0 ml) was purged with nitrogen for 5 minutes at 25° C. This mixture was then stirred at 100° C. for 3 hours, allowed to cool to ambient temperature, filtered and the filtrate evaporated under vacuum. The residue was purified on octadecylsilane reverse phase silica eluting with acetonitrile/water/trifluoroacetic acid (as a gradient from 30/69.8/0.2 to 50/49.8/0.2) and the product further purified by silica column chromatography eluting with dichloromethane/methanolic ammonia (7M) (90/10) to give 4-(2-carboxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (85 mg 36%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:36][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:38])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>O1CCCC1.CO>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([CH2:36][CH:37]([OH:38])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH2:34][CH2:35]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CC(=O)c4ccccc4)CC3)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CC(O)c4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(1-phenacylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (120 mg) in a mixture of tetrahydrofuran (1 ml) and methanol (0.2 ml) was added sodium borohydride (11 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1, 1% triethylamine) and dried under reduced pressure to give the title compound (90 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1I.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.[Cu-]=O.C1(C)C=CC=CC=1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[F:13])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Fc1ccccc1I
Reactant: Cc1ccc(C)n1-c1cc[nH]n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccn(-c2ccccc2F)n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (1.00 g) prepared according to the same procedures as Preparation 4 in N-methylpyrrolidone (10 ml) were sequentially added 1-fluoro-2-iodobenzene (1.08 ml), copper (I) oxide (89 mg), 8-quinolinol (180 mg) and cesium carbonate (4.04 g) at room temperature, and the mixture was stirred at 110° C. for 3 hours. This reaction mixture was cooled to room temperature, and then toluene was added thereto, and the mixture was filtered through Celite. The filtrate was sequentially washed with a 2N aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 10/1) to give the titled compound (1.19 g).
Reaction SMILES: O[C:2]([C:18]([F:21])([F:20])[F:19])([CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7])[CH2:3][OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:6]([CH3:8])([CH3:7])[CH2:5][C:2]2([C:18]([F:21])([F:20])[F:19])[CH2:3][O:4]2)[CH:14]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 g of 2-hydroxy-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-pentanol and 3.45 g of triphenylphosphine are dissolved in 50 ml of tetrahydrofuran and mixed in 3 portions at 0° C. with 2.5 ml of azodicarboxylic acid-diethyl ester. After one hour at 0° C., it is stirred for 16 more hours at room temperature, then refluxed for 7 hours and again stirred for 48 hours at room temperature. After concentration by evaporation, a hexane-isopropylether mixture is added, filtered, and the filtrate is chromatographed on silica gel. The product that is eluted with hexane/ethyl acetate is distilled on a bulb tube, boiling point 100° C./0.5 mbar.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:17])([CH3:4])([CH3:3])[CH3:2].C(C1CCCC([Cl:28])C1=O)(C)(C)C>>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:7]([Cl:28])[C:6]1=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: CC(C)(C)C1CC(c2ccccc2)CCC1=O
Product: CC(C)(C)C1CC(c2ccccc2)CC(Cl)C1=O

Procedure:
The chlorination of 2-tert-butyl-4-phenyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.O1CCCC1.C([BH3-])#N>C(O)(=O)C>[CH:10]1([NH:13][CH:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:2])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: CC(=O)c1ccccn1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(NC1CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
A mixture of 2-acetylpyridine (250 mg, 2.06 mmol), cyclopropylamine (111 mg, 1.94 mmol), anhyd tetrahydrofuran (15 mL) and acetic acid (1.5 mL) is stirred at room temperature for 10 min. MP-cyanoborohydride (1.2 g, 2.82 mmol) is added and the mixture is stirred overnight. The reaction is filtered through a Varian mega bond elut SCX and the resin washed with methanol (20 mL). The resin is then washed with 7 N methanolic ammonia (60 mL) and the eluent is evaporated. The residue is purified by chromatography on an ISCO Redisep 10 g cartridge eluting with ethyl acetate to afford cyclopropyl(1-pyridin-2-yl)ethylamine (245 mg, 73% yield) as oil. A hydrochloride salt is prepared by dissolving the amine (50 mg, 0.308 mmol) in methanol (2 mL), adding 1 M ethereal hydrochloric acid (0.8 mL), some methanol is removed, more ether added and the hydrochloride salt is collected by filtration (50 mg, 69% yield as gray solid). RT=1.69 min; MS 163 (M+1); 1H NMR (δ, ppm): 9.5 (2H, br s), 8.69 (1H, d), 7.94 (1H, dd), 7.69 (1H, d), 7.47 (1H, m), 4.59 (1H, q), 1.58 (3H, d), 0.6-0.96 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:41][CH2:42][CH2:43][F:44]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][CH2:43][F:44])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To 140 mg (0.30 mmol) of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-D-glutamate in 5 mL N,N-dimethylformamide were added 42 mg (0.3 mmol) of powdered potassium carbonate and 56 mg (0.30 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[C:5]([F:11])[CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[O:19]C.II>O1CCCC1.[Pd](Cl)Cl>[F:11][C:5]1[CH:4]=[C:3]([C:15]2[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([F:12])[CH:14]=2)[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(Br)cc1F
Reactant: COc1ccc([Mg]Br)cc1F
Agent: Cl[Pd]Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(O)c(F)c2)cc1F
Reaction time: 1 h

Procedure:
Flaky metallic magnesium (2.43 g) was added to 50 ml of dry tetrahydrofuran, and while the mixture was heated, a solution of 20.5 g of 4-bromo-2-fluoroanisole in 100 ml of dry tetrahydrofuran was added dropwise little by little in a stream of nitrogen to prepare a tetrahydrofuran solution of 3-fluoro-4-methoxy-phenyl magnesium bromide. Then, 18.0 g of 4-bromo-2-fluoroanisole was added to 100 ml of dry tetrahydrofuran containing 0.05 g of iodine and 0.1 g of palladium chloride. The mixture was maintained at 40° to 50° C. in a stream of nitrogen, and the above-prepared tetrahydrofuran solution of 3-fluoro-4-methoxyphenyl magnesium bromide was added dropwise gradually. The addition was completely in about 1 hour, and thereafter, the mixture was reacted for 5 hours at the refluxing temperature of tetrahydrofuran. After the reaction, the reaction mixture was after-treated in a customary manner to give 38.2 g of a crude product. The desired product was isolated from the crude product by silica gel column chromatography using ethyl acetate/hexane as an eluent. Thus, 15.0 g of 3,3'-difluoro-4,4'-dimethoxybiphenyl was obtained.
Reaction SMILES: Br[CH:2]([F:24])[C:3]([F:23])([F:22])[S:4][C:5]1[NH:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1.BrC[CH2+](C(F)(F)CF)C1NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1>>[C:16]1([C:7]2[N:6]=[C:5]([S:4][C:3]([F:22])([F:23])[CH2:2][F:24])[NH:9][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(Br)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: COc1ccc(-c2nc([CH2+](CBr)C(F)(F)CF)[nH]c2-c2ccc(OC)cc2)cc1
Product: FCC(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1

Procedure:
By substituting 2-(2-bromo-1,1,2-trifluoroethylthio)-4,5-diphenylimidazole for the 2-(2-bromo-1,1,2-trifluoroethylethio)-4,5-bis(4-methoxyphenyl)imidazole of Example 20, one obtains as product 4,5-diphenyl-2-(1,1,2-trifluoroethylthio)imidazole, m.p. 225°-226.5°.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C(O)(=O)C.CCOCC.O=[Pt]=O>[CH3:16][N:2]([CH3:1])[C:3](=[O:15])[CH2:4][N:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CN(CCc1ccncc1)CC(=O)N(C)C
Agent: O=[Pt]=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN(CCC1CCNCC1)CC(=O)N(C)C

Procedure:
Of the crude N,N-dimethyl-2-[methyl-(2-pyridine-4-yl-ethyl)-amino]-acetamide, 44 g are dissolved in 500 ml of glacial acetic acid and hydrogenated with 4 g of PtO2 at ambient temperature under 3 bar H2. After the catalyst has been removed by suction filtering the filtrate is evaporated down. The residue is made alkaline with 50% potassium hydroxide solution while cooling with ice and the product obtained is taken up in ether. The ether solution is dried over sodium sulphate, filtered and the solution is evaporated down. The product is left as a yellow oil. Yield: 42 g
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[O:12][CH3:13]>CCOCC.C1COCC1>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][C:6]=1[O:12][CH3:13]
Reactant: N#CBr
Reactant: COc1cc(N)ccc1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(NC#N)ccc1Br
Reaction time: 72 h
Yield: 25.5 %

Procedure:
A mixture of cyanogen bromide (0.550 g, 5.19 mmol) and 4-bromo-3-methoxyaniline (Lancaster Synthesis Inc., P.O. Box 1000, Windham, N.H. 03087-9977) (2.2 g, 11 mmol) in ether/THF (6 mL) was stirred for 3 days under nitrogen atmosphere. The reaction was filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using 9/1 Hexane/acetone to give (4-bromo-3-methoxyphenyl)cyanamide (0.300 g, 12%). HRMS: calcd for 2 C8H7BrN2O+H+, 452.95562; found (ESI-FT/MS, [2M+H]1+), 452.9556.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:19])[N:13]=[C:14]([CH2:17][OH:18])[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CCOC(C)=O>[CH3:21][S:22]([O:18][CH2:17][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:19])[N:13]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(CO)c2nc(C3CCC(C)(C)CC3)sc2n1
Solvent: CCOC(C)=O
Product: Cc1nc(COS(C)(=O)=O)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methanol (6.42 g) and EtOAc (65 mL) were added dropwise TEA (4.5 mL) and MsCl (2.1 mL) under ice-cooling, followed by stirring at 0° C. for 1 hour. The reaction mixture was filtered and then to the liquid was added saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to obtain [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl methanesulfonate (9.3 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)C=C.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>C(OCC)C>[CH2:24]([C:10]1[CH:9]=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CCOc1ccc(-c2ccccc2)cc1
Reactant: CN(C)c1ccccc1
Solvent: CCOCC
Product: C=CCc1cc(-c2ccccc2)ccc1O

Procedure:
A solution of 4-allyloxy-biphenyl 65 (5.03 g, 23.9 mmol) in 20 ml of dimethylaniline was heated at 170° C. for 5 hr. The mixture was diluted with 250 ml diethyl ether and washed with 1M HCl solution. The ether phase was washed with brine, dried and concentrated to give a brown solid. The crude product was recrystallized from cyclohexane to give 2.69 g 3-allyl-biphenyl-4-ol 66. The mother liquor was concentrated and chromatographed (7% ethyl acetate/hexane) to give an additional 2.13 g of 2-allyl-4-phenyl-phenol 66.