Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-methoxy-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>N1C=CC=CC=1>[Br:12][C:4]1[C:3]2[O:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[CH:15][C:2]=2[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=1
Reactant: C#CC1CC1
Reactant: CS(=O)(=O)c1cc(Br)c(O)c(Br)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1cc(Br)c2oc(C3CC3)cc2c1
Temperature: 130 °C
Yield: 49 %

Procedure:
To a solution of 2,6-dibromo-4-methylsulfonylphenol (1 g, 3.30 mmol) in pyridine (40 mL) was added ethynylcyclopropane (240 mg, 3.64 mmol) and Cu2O (260 mg, 1.82 mmol). The reaction mixture was degassed with N2. The mixture was heated to 130° C. for 3 hours. It was then concentrated and purified by column chromatography (PE to PE/EA=3/1) to give the title product (510 mg, 53%) as a gray solid. 1H NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.93 (s, 1H), 6.52 (s, 1H), 3.07 (s, 3H), 2.13-2.11 (m, 1H), 1.13-1.05 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:15]=1)[O:12][C:11]([N:28]1[CH2:33][CH2:32][O:31][C@H:30]([CH3:34])[CH2:29]1)=[CH:10][C:9]2=[O:35])=[O:5]>C(Cl)Cl>[CH3:34][C@@H:30]1[CH2:29][N:28]([C:11]2[O:12][C:13]3[C:8]([C:9](=[O:35])[CH:10]=2)=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:15][C:14]=3[CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH2:33][CH2:32][O:31]1
Reactant: COC(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C2CCCN2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Reaction time: 16 h
Yield: 81.6 %

Procedure:
HCl 4N (6.24 mL, 24.97 mmol) was added to a stirred solution of tert-butyl 2-(6-(methoxycarbonyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (1.18 g, 2.50 mmol) in DCM (10 mL) at room temperature and stirred for 16 h. the solvents were evaporated and DCM (5 mL) and MeOH (5 mL) were added followed by 10% methanolic ammonia (7 N) in dichloromethane (5 mL). The solid was filtered and washed with a 1:1 mixture of DCM and MeOH. The solvent was evaporated to dryness and the crude product was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness, triturated with diethyl ether to give a solid which was collected by filtration and dried under vacuum to give methyl 2-((R)-2-methylmorpholino)-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (0.760 g, 82%) as a white solid. Mass Spectrum: m/z [M+H]=373.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])/[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[C:31]([O:37][CH2:38]Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].[Cl-].[NH4+]>CN(C)C=O.ClCCl.CO.C(O)(=O)C>[CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:17])[CH3:18])=[O:14])/[C:9]([O:11][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.4 %

Procedure:
To a solution of 100 mg (0.347 millimole) of (Z)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoic acid in 1.0 ml of dimethylformamide were added 130 μl (0.87 millimole) of 1,8-diazabicyclo[5,4,0]-7-undecene and 75 μl (0.52 millimole) of chloromethyl pivalate, and the mixture was stirred at room temperature for 21 hours. Fifty milliliters of a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with 30 ml of ethyl acetate each time. The combined organic layers were washed with 10 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin-layer chromatography silica gel 60 F254 made by E. Merck & Co.; dichloromethane/methanol/acetic acid [30:1:1)] to give 90 mg (yield 64%) of the captioned compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=O.C1(C)C=CC(S([NH2:22])(=O)=O)=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]#[N:22])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1C
Temperature: 200 °C
Yield: 84.1 %

Procedure:
A mixture of 49 grams (295 millimoles) of 3-methoxy-4-methylbenzoic acid, 53.9 grams (315 millimoles) of p-toluene-sulfonamide, and 129 grams (619 millimoles) of phosphorus pentachloride was prepared and then heated at 200° C. while stirring. Phosphorus oxychloride was distilled at 106°-112° C.; and the mixture was further heated at 200° C. while stirring until no distillated came out. To the reaction mixture was added while stirring and cooling with ice 120 milliliters of pyridine in small portions and further 550 milliliters of water. Crystals precipitated were separated by filtration, suspended in 200 milliliters of a 5% aqueous sodium hydroxide solution, and then stirred at room temperature for 30 minutes. These crystals were separated by filtration and the crude product thus obtained was purified by steam distillation to obtain 36.5 grams of 3-methoxy-4-methylcyano-benzene (yield, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.Br.C(O)(=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: COc1ccc(Oc2cc(Cl)ccc2C)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(Cl)cc1Oc1ccc(O)cc1

Procedure:
4-chloro-o-cresol and 4-bromoanisole yield p-(p-chloro-o-tolyloxy)anisole of b.p. 112°-116° C./0.04 Torr and reaction with hydrobromic acid/acetic acid yields p-(p-chloro-o-tolyloxy)phenol; m.p. 83°-85° C.;
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.P(Br)(Br)([Br:13])=O.[OH-].[Na+]>>[Br:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccnc2ccsc12
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccnc2ccsc12
Yield: 59.3 %

Procedure:
Heat thieno[3,2-b]pyridin-7-ol (5.00 g, 33 mmol) and phosphorus oxybromide (50 g, 174 mmol) together at 110° C. for 3 h. Pour the hot reaction mixture into a mixture of ice and 5 N NaOH and extract with CH2Cl2. Dry the organic portion over Na2SO4 and evaporate. Purify the resulting crude material using a silica gel chromatography column (hexane:EtOAC=3:1) to give the title compound (4.19 g, 59%). ES/MS m/z (81Br) 215 (M+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[I:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:24])=[CH:18]/[C:19](OCC)=[O:20])=[CH:13][CH:12]=1>>[I:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:24])=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(I)cc1

Procedure:
(E)-3-(4-Iodophenyl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) by a procedure analogous to that described in example 50b.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn](C)(C)C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[C:17]1[S:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=1.C(OCC)(=O)C>C1COCC1>[CH2:22]([C:19]1[S:18][C:17]([C:9]2[O:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)=[CH:21][CH:20]=1)[CH3:23]
Reactant: CCc1ccc(Br)s1
Reactant: COc1cccc2oc([Sn](C)(C)C)cc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2cc3c(OC)cccc3o2)s1
Yield: 41.8 %

Procedure:
To a solution of 4-methoxy-2-(trimethylstannyl)benzo(b)furan (3.00 g) and 2-bromo-5-ethylthiophene (1.84 g) in THF (25 ml) was added bistriphenylphosphinepalladium dichloride (224 mg), and the mixture was stirred with refluxing overnight. After cooling, ethyl acetate was added to the reaction mixture and the mixture was filtered through celite. The filtrate was washed with water and saturated brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.04 g) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=[O:4].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2C)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:51][CH2:50][N:49](C)[CH2:48][CH2:47]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH2:64]C2CCCC2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:47][CH2:48][NH:49][C:50](=[O:4])[CH2:51]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH3:64])=[CH:37][CH:38]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 17) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 471.1801, calculated for C24H28N4O4Cl [(M+H)+]471.1794.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:19][CH:18]([N:3]1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:5][N:1]=[N:2]1)[CH3:20]
Reactant: CC(C)I
Reactant: CCOC(=O)c1cn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnnn1C(C)C
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2H-1,2,3-triazole-4-carboxylate (1.5 g), potassium carbonate (2.64 g) and 2-iodopropane (1.91 ml) in dry acetonitrile (30 ml) was stirred at 50-60° C. under nitrogen for 2 h. Further 2-iodopropane (0.955 ml) was added and the mixture was stirred at 50-60° C. under nitrogen for 1.5 h. The mixture was cooled to room temperature and allowed to stand for 4 days. The mixture was filtered through a 2 g silica SPE column eluting with ethyl acetate. The solution was concentrated in vacuo, Purification by chromatography on silica gel (100 g cartridge), eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 40 min gave the title compound (315 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1([CH2:16][CH:17]=C)[S:13](=[O:15])(=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C[OH:20].C(Cl)(Cl)Cl>>[CH2:1]([NH:3][C:4]([C:6]1([CH2:16][CH:17]=[O:20])[S:13](=[O:15])(=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC1(C(=O)NCC)Cc2ccsc2S1(=O)=O
Reactant: CO
Solvent: ClC(Cl)Cl
Product: CCNC(=O)C1(CC=O)Cc2ccsc2S1(=O)=O
Temperature: 25 °C

Procedure:
N-Ethyl-2-allyl-2,3-dihydrothieno[2,3-b]thiophene-2-carboxamide-1,1-dioxide (7.2 g, 0.025 mol) in 1:1 methanol-chloroform (300 mL) was cooled to -78° C. Ozone was bubbled into the reaction mixture until a pale blue color persisted. The reaction was sparged with nitrogen for 10 minutes and dimethyl sulfide (7 mL) was added. The solution was warmed to room temperature and the solvents removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solution was filtered, and the solvent evaporated to give the title compound as an oil (5.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:16](=[O:19])[CH2:17][CH3:18])[CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: COc1c(C)cccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1cc(C)c(OC)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
13.6 g of 2,6-dimethylanisole was dissolved in 30 ml of methylene chloride, and 16 g of anhydrous aluminum chloride was added. Then, with water cooling, 11 g of propionyl chloride was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the organic layer was separated and washed with water. The solvent was evaporated to give 18.7 g of 2,6-dimethyl-4-propionylanisole.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[C:48]3[NH:54][CH:53]=[CH:52][C:49]3=[N:50][CH:51]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH:54]1[C:48]2[C:49](=[N:50][CH:51]=[C:46]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:21]=[CH:22][C:23]([C:26]4([NH2:30])[CH2:29][CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[CH:47]=2)[CH:52]=[CH:53]1
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC1(c2ccc(-c3c(-c4cnc5cc[nH]c5c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 71.7 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (44 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. The fraction was evaporated to dryness. Step 2: The residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL) was added. After overnight reaction, the mixture was evaporated and the residue was purified by HPLC to give the titled compound as a white solid (32 mg, 60%). 1HNMR (DMSO-d6) 400 MHz δ: 11.39 (s, 1H), 8.58 (s, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.25 (s, 1H), 8.09 (dd, J=4.6, 1.7 Hz, 1H), 7.99 (dd, J=8.0, 1.7 Hz, 1H), 7.89 (d, J=1.1 Hz, 1H), 7.63 (t, J=3.2 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.36 (td, J=7.4, 1.7 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.13 (t, J=7.4 Hz, 1H), 6.90 (dd, J=7.7, 1.4 Hz, 1H), 6.75 (dd, J=8.0, 4.6 Hz, 1H), 6.51-6.49 (m, 1H), 2.48-2.41 (m, 2H), 2.26-2.19 (m, 2H), 2.11-2.02 (m, 1H), 1.77-1.68 (m, 1H); LCMS: 496 [M+H].
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[CH:14]=[C:13](Cl)[N:12]=1>C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[CH:14]=[C:13]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(OC1CCCCC1)c1cc(Cl)nc(Cl)n1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
A cold (0° C.) solution of cyclohexanol (2.35 ml; 22.3 mmol) was treated with sodium hydride (534 mg; 22.3 mmol) in dry THF (25 ml) and stirred for 30 min at 0° C. It was slowly added to a cooled (0° C.) solution of cyclohexyl 2,6-dichloropyrimidine-4-carboxylate (Intermediate 31, 3.50 g; 12.72 mmol) in dry THF (70 ml) and the resulting mixture was stirred at 50° C. After 4 h the reaction was treated again with a solution cyclohexanol (0.34 ml; 3.18 mmol) and sodium hydride (76.3 mg; 3.18 mmol) in dry THF (3 mL) obtained as described above and it was stirred for an additional hour. The reaction mixture was concentrated under vacuum and the residue was taken up in EtOAc and the organic layer was washed with water, then brine, dried over MgSO4, filtered off and concentrated under vacuum to afford the title compound (4.80 g, 99%) without further purification.
Reaction SMILES: [O:1]([CH:13]([CH3:15])[CH3:14])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1C(CCCCC(N)=O)SSC1>CC(=O)CC>[C:16]([O:12][CH2:11][C@H:9]1[O:10][C@H:2]([O:1][CH:13]([CH3:15])[CH3:14])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC(C)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCC(=O)O
Agent: NC(=O)CCCCC1CCSS1
Solvent: CCC(C)=O
Product: CCCCCCCC(=O)OC[C@H]1O[C@H](OC(C)C)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 48 h
Yield: 68.9 %

Procedure:
To a stirred solution of isopropyl α-D-glucopyranoside (1.1 g, 5 mmol) and octanoic acid (0.9 g, 6.25 mmol) in 100 ml 2-butanone was added immobilized lipase (0.5 g Lipozyme™, see example 8). Stirring was continued at 60° C. for 48 hours. The enzyme was removed by filtration and the solvent was removed in vacuo followed by chromatography yielding 1.2 g (70%) of the product 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J=6.7 Hz, 3H); 1.19 (d, J=6.1 Hz, 3H); 1.24 (d, J=6.2 Hz, 3H); 1.28 (m, 8H); 1.62 (m, 2H); 2.34 (m, 2H); 3.35 (t, J=9.4 Hz, 1H); 3.50 (dd, J=4.0 and 9.5 Hz, 1H); 3.73 (t,J=9.3 Hz, 1 H); 3.85 (m, 1H); 3.92 (m, 1H) 4.35 (m, 2H); 4.96 (d, J=3.9 Hz, 1H).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([N:67]2[CH2:72][CH2:71][CH:70]([NH2:73])[CH2:69][CH2:68]2)=[CH:63][C:62]=1[C:74]([F:77])([F:76])[F:75])([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([N:67]2[CH2:68][CH2:69][CH:70]([NH:73][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:71][CH2:72]2)=[CH:63][C:62]=1[C:74]([F:77])([F:75])[F:76])([O-:60])=[O:59]
Reactant: NC1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)NC1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (17 μL; 0.1 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 1-(4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-ylamine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 72) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 90 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (27 mg; 0.05 mmol). The structure was confirmed using Protocol I-B. Calculated mass=588; observed mass=588; HPLC retention time=5.09 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([F:29])[C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[C:22]([F:29])=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(Cl)cc1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=463.2 [M+H]+.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=[O:28])C.Cl>O>[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hexamethylene tetramine (14.0 g) was added to a mixture of 3-phenoxybenzyl chloride (10.9 g), glacial acetic acid (25 ml) and water (25 ml) under a nitrogen atmosphere and the mixture refluxed for 2.5 hours, after which concentrated hydrochloric acid (20 ml) was added and the refluxing continued for a further 15 minutes. The mixture was cooled to the ambient temperature, extracted with diethyl ether and the extracts washed with water, saturated sodium bicarbonate solution, and finally with water. After drying the ethereal solution over anhydrous magnesium sulphate, the ether was evaporated under reduced pressure to yield 3-phenoxybenzaldehyde, identified by comparison with an authentic sample.