Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[O:24]COC)[CH3:2].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[OH:24])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1OCOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1O
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of 4-(3-cyano-5,6-difluoroindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester (0.12 g) in a mixed solvent of tetrahydrofuran (1.5 mL) and ethanol (3 mL) was added 2 mol/L hydrochloric acid (1.0 mL), and this mixture was stirred at 70° C. overnight. After cooling to ambient temperature, the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give the title compound (0.074 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([NH:16][NH2:17])[CH:13]=[C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:11]=1.[C:24]1([CH3:32])[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O)(=O)C>CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([NH:16][N:17]=[CH:32][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH:13]=[C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:11]=1
Reactant: Cc1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)nc(OCCc2ccccn2)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(OCCc3ccccn3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-[2-(pyridin-2-yl)-ethoxy]-4-hydrazino-6-(morpholin-4-yl)-pyrimidine (Product 3) (5 g, 15.8 mmol, 95% purity), m-tolualdehyde (1.99 g, 16.6 mmol), ethyl acetate (25 mL) and acetic acid (45 μL) was heated to reflux for 15 minutes to give a clear solution. When TLC indicated that the reaction was completion, the reaction was allowed to cool to room temperature causing a solid precipitate to formed. The creamy solid was filtered out, washed with ethyl acetate (EtOAc) (3×5 mL) and dried to obtain crude Compound 6. The crude product (5 g, 75.6%) was dissolved in EtOAc (34 mL) under reflux. The resulting clear solution was concentrated to about 20 mL and cooled to room temperature causing Compound 6 to precipitate out forming a suspension. The suspension was stirred for 2 hours, then the precipitate was filtered out, washed with EtOAc (2×10 mL) and vacuum-dried to give Compound 6 as an off-white solid, 4.1 g (82%).
Reaction SMILES: CS(C)=O.C[C:6]([CH3:9])([O-])[CH3:7].[K+].[OH2:11].[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH:7]([O:11][CH:14]1[CH2:13][CH2:12][CH2:17][CH2:16][CH2:15]1)=[CH:6][CH3:9]
Reactant: O
Reactant: CC(C)(C)[O-]
Reactant: CCCCCC
Agent: [K+]
Solvent: CS(C)=O
Product: CC=COC1CCCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 855.8 %

Procedure:
A mixture of 280 g of the crude product, 300 g of dimethyl sulfoxide, and 22.5 g (0.2 mol) of potassium t-butoxide was heated at 100° C. on the oil bath and ripened for 2 hours at the temperature. The solution was allowed to cool, and 650 g of water and 600 g of n-hexane were added thereto, from which the organic layer was collected. The organic layer was washed with 250 g of water, and the solvent was distilled off in vacuum, leaving 300 g of an oily substance. The oily substance was subjected to vacuum distillation, obtaining 240 g of the end product, cyclohexyl propenyl ether. The yield was 86% (two steps) and the purity was 99.0% as analyzed by gas chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2N(CC3C=CC=CC=3)N=CC=2CC1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:18]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=2)=[N:13]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(C#N)cc3)nn(Cc3ccccc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2cnn(Cc3ccccc3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 43, Step C, 0.30 g) in 9 mL of 1,4-dioxane was added 0.20 g of K3PO4, 0.10 g of 4-cyanophenylboronic acid, and 0.05 g of PdCl2dppf. The mixture was heated at reflux for 72 h. The mixture was filtered through diatomaceous earth and concentrated in vacuo to give 0.33 g of an orange solid. Chromatography on SiO2 (5 to 30% EtOAc/hexanes) afforded 0.21 g of a 7:1 mixture of 1-benzyl-3-(4-cyano-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and a side product, 1-benzyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The mixture of compounds (0.21 g) was dissolved in 7 mL CH2Cl2 and 7 mL of TFA was added. The mixture was stirred at RT for 1 h and concentrated in vacuo. The crude product was dissolved in CH2Cl2 and treated with Dowex® 550A resin. After stirring for 2 h, the mixture was filtered and concentrated in vacuo. Chromatography using a C18 reverse phase column afforded 0.14 g of the title compound as its TFA salt. MS (ESI): exact mass calculated for C21H20N4, 328.17. found, m/z 329.1 [M+H]+, 351.1 [M+Na]+. 1H NMR (500 MHz, CD3OD): 7.83-7.81 (m, 2H), 7.76-7.74 (m, 2H), 7.36-7.28 (m, 3H), 7.19-7.17 (m, 2H), 5.46 (s, 2H), 3.39-3.37 (m, 4H), 3.15-3.09 (m, 4H).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]1[CH:11]=[C:12]([C:17]2[O:18][C:19](=[O:22])[CH2:20][N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16].O.[OH-].[Li+]>C1COCC1.O>[F:9][C:10]1[CH:11]=[C:12]([C:17]2[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[C:20]([C:19]([OH:22])=[O:18])[N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: O=C1CN=C(c2ccc(F)c(F)c2)O1
Reactant: COC1=NCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc(F)c(F)c2)n2c1CCCC2
Temperature: 90 °C
Yield: 70.2 %

Procedure:
6-methoxy-2,3,4,5-tetrahydropyridine (0.431 g, 3.80 mmol) was dissolved in THF (5 mL) in a 40 mL screw-cap vial and 2-(3,4-difluorophenyl)oxazol-5(4H)-one (0.75 g, 3.80 mmol) in THF (5 mL) was added, producing an orange solution. The vial was capped and heated to 90° C. for 3 hours. THF was removed under reduced pressure and the residue was dissolved in MeOH (10 ml) and lithium hydroxide monohydrate (0.479 g, 11.41 mmol) in water (1 mL) was added. The reaction was heated to 90° C. for 3 hours. MeOH was removed by evaporation under reduced pressure. The remaining aqueous solution was diluted with water (5 mL) and acidified to pH 2 with 5M HCl. The solution was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to yield the desired product as a brown oil (742 mg, 71%) that was used without further purification. LCMS (+ESI) m/z: 279.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[O:14].[CH:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH3:38])=[CH2:25].C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:14]2)=[C:30]1[CH3:38])=[CH2:25]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: C=COCCn1c(C)cc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=COCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 70 °C
Yield: 76.1 %

Procedure:
A mixture of 15.6 g of 2-(2-methyI-4-diethylaminophenyl)carbonylbenzoic acid, 12.5 g of 1-(2-vinyloxyethyl)-2-methylindole, and 50.0 ml of acetic anhydride was maintained at approximately 70° C. for approximately four hours. The resulting solution was cooled to ambient temperature and slowly poured into a mixture of toluene and 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed successively once each with water and saturated sodium chloride solution and evaporated to dryness. The residue that remained was heated in a 1:1 mixture of isopropyl alcohol:hexane. The liquid was decanted from a gummy residue. The residue was dissolved in 100.0 ml of acetone and the resulting solution was added dropwise to 1500.0 ml of 2 percent aqueous ammonium hydroxide. The solid which precipitated was collected by filtration, washed with water and dried to obtain 18.86 g of 3-[1-(2-vinyloxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula I: R1 =CH2 =CHOC2H4 ; R1 =R2 =CH3 ; R3 =R4 =C2H5 ; X=Y=H), a tan-colored solid which melted over the range 135°-141° C. Significant infrared maxima appeared at 1760 (C=O;s) and 1120 (C--O;s)cm A toluene solution of the product spotted on an acid clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH3:13])[C:10]2[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=3)[CH:7]=[CH:6][C:5]=2[C:4](=[O:26])[C:3]=1[C:27](=[O:30])[NH:28][CH3:29].C1COCC1.CO.O.[OH-].[Li+].Cl>O>[NH2:1][C:2]1[N:11]([CH2:12][CH3:13])[C:10]2[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH:7]=[CH:6][C:5]=2[C:4](=[O:26])[C:3]=1[C:27](=[O:30])[NH:28][CH3:29]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(=O)c(C(=O)NC)c(N)n(CC)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(-c3ccc(CC(=O)O)cc3)nc21
Temperature: 70 °C
Yield: 97.6 %

Procedure:
To a suspension of 0.87 g (2.1 mmol) of the compound obtained from step 2.4 in a 1/1/1 mixture of THF/methanol/water (12 ml) is added 0.134 g (3.2 mmol) of lithium hydroxide in a single portion. The reaction mixture is heated at 70° C. for 3 hours, and then cooled to room temperature. Water (10 ml) is added and the medium is acidified with HCl solution (1N) to pH 2, and the precipitate formed is isolated by filtration and dried over P2O5. 0.78 g of product is obtained in the form of a white powder. Yield=96%. Melting point 260° C. MH+: 381.1 (tr: 6.74 min., condition 1).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]#[N:30]>C1COCC1.C1COCC1.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]#[N:30]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (15.8 mg of a 60% dispersion in mineral oil, 0.411 mmol) in dry THF (2 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.06 g, 0.294 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 4-chloro-3-cyano-benzenesulfonyl chloride (97.1 mg, 0.411 mmol) in dry THF (3 ml). Stirring continued at 0° C. for 15 minutes and then the reaction mixture is poured onto water (30 ml) and extracted with ethyl acetate (100 ml). The organic portion is separated and washed brine (50 ml), dried (MgS04) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+404)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)[CH:17]=[CH2:18]>>[CH2:18]([C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH:17]=[CH2:16]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Product: C=CCc1cc(C(=O)c2ccccc2)ccc1O
Yield: 46.2 %

Procedure:
4-hydroxybenzophenone (25 g) was converted to 4-allyloxybenzophenone (29.2 g, yellow solid) by the procedure of Example 23. Claisen rearrangement using that procedure gave 13.5 g (47%) of desired 3-allyl-4-hydroxybenzophenone, the balance being recovered. Finally, acylation of 3-allyl-4-hydroxybenzophenone (5.9 G) according to general procedure of Example 1 produced 6.9 g (86%) of product as yellow solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:15]([Cl:16])=[CH:14][C:13]([N:17]([C:22]2[C:41]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][C:25]3[C:26]([C:36](=[O:39])[NH:37][CH3:38])=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BrH:45]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:45][C:6]1[C:15]([Cl:16])=[CH:14][C:13]([N:17]([C:22]2[C:41]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][C:25]3[C:26]([C:36](=[O:39])[NH:37][CH3:38])=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Sodium nitrite (0.17 g, 2.42 mmol) was added to a 0° C. solution of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.29 g, 2.20 mmol) in acetonitrile (7.3 ml) and 48% aqueous HBr (7.3 ml) at 0° C. and the reaction mixture was stirred at 0° C. for 30 mins, Copper(I) bromide (0.38 g, 2.64 mmol) was added and the solution was heated at 50° C. for 30 mins. The reaction mixture was cooled to RT, diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.24 g, 86%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86-7.93 (m, 2H), 7.50-7.63 (m, 4H), 7.17-7.25 (m, 2H), 5.79 (br. s., 1H), 3.92 (s, 3H), 3.28 (s, 3H), 3.01 (d, J=4.88 Hz, 3H), 1.94-2.04 (m, 1H), 0.76-1.09 (m, 3H), 0.55 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([O:21][CH3:22])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl.O=S(Cl)Cl.[CH3:31]O>>[ClH:19].[CH2:1]([O:2][C:3](=[O:23])[C@H:4]([O:21][CH3:22])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:31]
Reactant: COC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) is added 2M NaOH aqueous solution (5 mL). After being stirred at room temperature for 2 h, the reaction mixture is acidified with 2M HCl and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in EtOH (5 mL) and treated with SOCl2 (0.252 mL, 3.26 mmol). After being stirred at 55° C., the reaction mixture was concentrated. The residue is used for a next step without further purification. HPLC retention time=1.49 minutes (condition A): MS (m+1)=348.2
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH2:23][CH2:24]O)[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([O:8]COC)[C:4]([F:7])([F:6])[F:5].[O:33]1C2C=CC(C3(C)N=CN=C3)=CC=2OC1.C[CH:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2([CH3:65])[NH:62][C:61](=[O:63])[NH:60][C:59]2=[O:64])=[CH:54][CH:53]=1)C>>[O:51]1[C:52]2[CH:57]=[CH:56][C:55]([C:58]3([CH3:65])[NH:62][C:61](=[O:63])[N:60]([CH2:24][CH2:23][C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:15]5[CH:26]=[CH:27][C:12]([C:3]([OH:8])([C:4]([F:5])([F:6])[F:7])[C:2]([F:31])([F:32])[F:1])=[CH:13][C:14]=5[CH2:28][CH2:29][CH3:30])[CH:18]=4)[C:59]3=[O:64])=[CH:54][C:53]=2[O:33][CH2:49]1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CCO)c1
Reactant: CC1(c2ccc3c(c2)OCO3)C=NC=N1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CCN2C(=O)NC(C)(c3ccc4c(c3)OCO4)C2=O)c1

Procedure:
2-(3-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) phenyl)ethanol was used in place of 1-(3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propyl phenoxy)phenyl) ethanol; and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazol dine-2,4-dione was used in place of 5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione for a similar operation as Example 27 b), and the title compound was obtained as a colorless oil.
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][C@@H:56]([N:58]2[CH2:63][CH2:62][CH:61]([OH:64])[CH2:60][CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][CH:61]1[CH2:62][CH2:63][N:58]([C@@H:56]([CH3:55])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:59][CH2:60]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119, see example 80) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (35.0 g, 172.4 mmol) in methanol (400 mL) and tetrahydrofuran (200 mL) was added sodium borohydride (6.5 g, 172.4 mmol) in portions at about 0° C. The mixture was stirred for about 3 h while being allowed to warm to ambient temperature. The solvents were removed under vacuum, the residue was diluted with water (600 mL) and was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to provide the desired product. MS (DCI-NH3): m/z 204, 206 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:28])([CH2:25][CH:26]=[CH2:27])[CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH2:25]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:28][C:37](=[O:39])[N:11]([C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]2)[CH2:10][CH2:9]1)[CH:26]=[CH2:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCC1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a solution of (3S)-tert-butyl 3-(3-(4-fluorophenyl)-3-hydroxyhex-5-enylamino)-piperidine-1-carboxylate (500 mg, 1.27 mmol) and triethylamine (515 mg, 5.1 mmol) in dried methylene chloride (13 mL) at 0° C. was added triphosgene (126 mg, 0.42 mmol). The mixture was stirred at room temperature till the reaction was over. Water was added, and the layers were separated. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water, dried over Na2SO4, and condensed to give the crude product, which was purified by column chromatography on silica gel to afford (3S)-tert-butyl 3-(6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (70 mg, 13%). 1H NMR: (CDCl3): 1.37 (d, 9H), 1.43 (m, 1H), 1.64 (m, 1H), 2.22 (m, 2H), 2.64 (m, 5H), 3.11 (m, 1H), 3.91 (broad, 3H), 5.00 (q, 2H), 5.65 (m, 1H), 6.99 (t, 3H), 7.20 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][Br:10])[CH2:2][CH3:3].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:14]([O:15][CH3:19])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][Br:10])[CH2:2][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1OC
Yield: 94.2 %

Procedure:
3.15 g (0.01 mole) of 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)1-bromopropane was dissolved in 50 ml of dry acetone. To this solution was added 2.75 g (0.02 mole) of anhydrous potassium carbonate and 3 g (0.02 mole) of methyl iodide. After refluxing for four days under an argon atmosphere, the reaction mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with 2% ethyl acetate/toluene to give 3.1 g (94%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:13][C:14]1[C:18](B(O)O)=[C:17]([CH3:22])[O:16][N:15]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:13][C:14]1[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[N:3][CH:4]=2)=[C:17]([CH3:22])[O:16][N:15]=1
Reactant: Cc1nc(N)cs1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1nc(Nc2ncc(-c3c(C)noc3C)c3sc(C)nc23)cs1

Procedure:
The title compound, MS: m/e=358.1 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3,5-dimethylisoxazole-4-boronic acid and 4-amino-2-methylthiazole (Example C).