Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33](=[O:35])[CH2:32][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:23]3[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=3[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1OCc1ccc(CC(=O)O)cc1
Reactant: CCCCCCCNCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
N-[2-(4-Chlorophenyl)ethyl]-N-heptylamine (0.127 g, 0.500 mmol) was dissolved in DMF (10 ml), (4-{[2-(methoxycarbonyl)phenoxy]methyl}phenyl)acetic acid (0.150 g, 0.500 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.176 g, 0.549 mmol) and N-ethyl-N,N-diisopropylamine (0.136 g, 1.049 mmol) was added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.224 g of methyl 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)-amino]-2-oxoethyl}benzyl)oxy]benzoate (yield 83.7%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>C(O)(=O)C>[ClH:25].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccccc3)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(Oc3ccccc3)cc2C1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-phenoxyindan (120 mg, 0.36 mmol), 4N hydrochloric acid-dioxane (1.7 ml) and acetic acid (5.1 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol) having the following physical properties:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([Si:27]([CH3:29])([CH3:28])[O:14][C:12]1[CH:13]=[C:8]([C:7]([CH3:17])([CH3:16])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=[CH:10][C:11]=1[F:15])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9 mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was added imidazole (1.34 g, 19.7 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of sodium carbonate (2×100 mL) and sodium chloride (2×100 mL). The organic phase was dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.50 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.92 (s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H), 6.80-6.83 (m, 1H), 6.87-6.92 (m, 1H). MS (EI): 370.2 [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]=1[C:9]#N.[H-].C([Al+]CC(C)C)C(C)C.C([O:23]CC)C>ClCCl>[CH3:1][C:2]1[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]=1[CH:9]=[O:23]
Reactant: CCOCC
Reactant: CC1=C(C#N)C(C)(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC1=C(C=O)C(C)(C)CC1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of the product of Example 8g (600 mg, 4.44 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under argon was added diisobutyl aluminum hydride (1.0 M in hexane, 8.9 mL, 8.9 mmol). The reaction was kept at −78° C. for 2 hours. The mixture was diluted with diethyl ether (150 mL) and quenched by addition of wet sodium sulfate. The mixture was then stirred for 30 minutes, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1->20/1) to afford the title compound as a light yellow liquid (420 mg, Yield: 68%). 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 2.45 (t, J=7.4 Hz, 2H), 2.10 (s, 3H), 1.67 (t, J=7.4 Hz, 2H), 1.22 (s, 6H) ppm.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.C[O-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]CCO)=[CH:15][C:14]=1[CH3:23].[Cl-].[NH4+]>CO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:7][CH2:6][O:5][C:1]2=[O:8])=[CH:15][C:14]=1[CH3:23]
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(NCCO)ccc1Br
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(N2CCOC2=O)ccc1Br
Temperature: 110 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
Diethyl carbonate (18 ml) and a 28% solution of sodium methoxide in methanol (1.1 ml, 5.70 mmol) were added to 2-(4-bromo-3-methyl-phenylamino)-ethanol (1.21 g, 5.27 mmol), and the mixture was heated with stirring at 110° C. for 15 hours. Further, methanol (16 ml) was added to the reaction solution, and the mixture was heated with stirring at 110° C. for one hour. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was triturated with hexane to give 3-(4-bromo-3-methyl-phenyl)-oxazolidin-2-one (989 mg, 73%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1)[NH2:21]
Reactant: Cn1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccccc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-phenyl-amine and hydrazine monohydrate.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>O1CCCC1>[C:12]([O:14][C:7](=[O:9])[CH2:8][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])([CH3:15])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)CC(=O)OC(C)(C)C
Yield: 25.9 %

Procedure:
3,3-Dimethylglutaric anhydride (455 mg, 3.2 mmol) in tetrahydrofuran (THF, 5 mL) was treated with sublimed potassium t-butoxide (395 mg, 3.5 mmol). After 30 min the solution was concentrated, poured into saturated NaHCO3 solution and washed with ether. The aqueous phase was acidified to pH 4 with 0.5M H3PO4 and extracted with chloroform which was dried over Na2SO4 and evaporated to afford 179 mg (26%) of the desired product as an oil. NMR (300 MHz, CDCl3, ppm), 1.13 (s, 6H), 1.47 (s, 9H), 2.33 (s, 2H), 2.45 (s, 2H).
Reaction SMILES: NC1C=C(OC)C=C(OC)C=1C(N)=O.OCCC1C=C(C=CC=1OCOC)C=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:46][CH2:47][CH2:48][C:49]1[CH:50]=[C:51]([C:59]2[NH:68][C:67](=[O:69])[C:66]3[C:61](=[CH:62][C:63]([O:72][CH3:73])=[CH:64][C:65]=3[O:70][CH3:71])[N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55]COC.S(=O)(=O)(O)O>CN(C)C(=O)C.O.C(O)(=O)C>[OH:55][C:54]1[CH:53]=[CH:52][C:51]([C:59]2[NH:68][C:67](=[O:69])[C:66]3[C:61](=[CH:62][C:63]([O:72][CH3:73])=[CH:64][C:65]=3[O:70][CH3:71])[N:60]=2)=[CH:50][C:49]=1[CH2:48][CH2:47][OH:46]
Reactant: COCOc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1CCO
Agent: COCOc1ccc(C=O)cc1CCO
Agent: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(CCO)c3)nc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1.4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[C:30]([F:33])([F:32])[F:31]>O1CCCC1.CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=2[C:30]([F:31])([F:33])[F:32])[C:10]1=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN2CC[C@H](NC(=O)OC(C)(C)C)C2=O)c(C(F)(F)F)c1

Procedure:
669 mg of (S)-3-(t-butoxycarbonylamino)pyrrolidin-2-one (J. Med. Chem., 1999, 42, 3557-3571) was dissolved in 30 ml of tetrahydrofuran/N,N-dimethylformamide (9:1) and the mixture was stirred under ice cooling. 60% sodium hydride was added thereto and the mixture was stirred for 20 minutes. A solution (3 ml) of ethyl 4-(bromomethyl)-3-trifluoromethylbenzoate (Reference Example 2 (step 2)) in tetrahydrofuran was added dropwise, followed by stirring at room temperature for 6 hours after removing an ice bath. The reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 867 mg of the objective compound as pale yellow crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:11]1[C:10](=[O:14])[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[N:12]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1cc(Oc2ccccc2)cn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
A solution of 5-phenoxy-2H-pyridazin-3-one (1.42 g, 7.54 mmol) in tetrahydrofuran (37.7 mL, 0.2M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (362 mg, 9.05 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.95 g, 8.30 mmol). The reaction was then warmed to 50° C., where it stirred for 18 h. After this time, the reaction was partitioned between water (300 mL) and methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (Isco 40 g, 20% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.72 g, 66%) as a clear oil; ES+-HRMS m/e calcd for C19H22N2O4 [M+H+] 343.1653, found 343.1652.
Reaction SMILES: [CH:1]([CH:4]1[C:10]2=[C:11]3[C:15](=[CH:16][CH:17]=[C:9]2[O:8][CH2:7][CH2:6][NH:5]1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]3)([CH3:3])[CH3:2].C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:1]([CH:4]1[C:10]2=[C:11]3[C:15](=[CH:16][CH:17]=[C:9]2[O:8][CH2:7][CH2:6][N:5]1[CH3:29])[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]3)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)C1NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)C1c2c(ccc3c2ccn3S(=O)(=O)c2ccccc2)OCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
1-Isopropyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 93, 25 mg, 0.068 mmol) was dissolved in methanol (4 mL) and formaldehyde (37 wt. % in H2O, 0.090 mL, 1.1 mmol) was added followed by sodium triacetoxyborohydride (72 mg, 0.34 mmol). The reaction mixture was allowed to stir at room temperature overnight, evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1.4 mg). MS m/z 385 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C1COCC1>[Br:14][C:12]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2)=[C:4]([CH2:3][NH:2][C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])[CH:13]=1
Reactant: COc1nc2cc(Br)cc(CN)c2nc1OC
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1nc2cc(Br)cc(CNC(=O)c3ccco3)c2nc1OC

Procedure:
300 mg (1 mmol) of 5-aminomethyl-7-bromo-2,3-dimethoxy-quinoxaline hydrochloride, 124 mg (1.1 equiv.) of furan-2-carboxylic acid, 212 mg (1.1 equiv.) of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 12.2 mg (0.1 equiv.) of 4-dimethylamino-pyridine are stirred in dried THF at 20° C. for 20 hours. The mixture is poured onto water, and the solid is filtered off and washed with water and diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[O:29]1CCC[CH2:30]1>>[F:28][C:26]1[CH:27]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH2:11][CH2:10]3)[C:30](=[O:29])[NH:1]2)=[CH:24][CH:25]=1
Reactant: C1CCOC1
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cc(F)ccc3c2=O)CC1
Yield: 30 %

Procedure:
A mixture of 2.2 parts of 2-amino-4-fluoro-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 1.2 parts of 1,1'-bis[1H-imidazol-1-yl]methanone and 45 parts of tetrahydrofuran is stirred and refluxed for 3 hours. The reaction mixture is cooled and the solvent is evaporated. The residue is boiled in 4-methyl-2-pentanone. The solid product is filtered off and crystallized from N,N-dimethylformamide, yielding 0.8 parts (30%) of 7-fluoro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 248° C.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11](O)=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1[C:10]2[C:5](=[C:6]([CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2ncccc12
Temperature: 70 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a solution of quinoline-5-carboxylic acid (500 mg, 2.83 mmol) in THF (10 mL) was added slowly LiAlH4 (1.0 M, THF) solution at 0° C. The resulting residue was heated to 70° C. for 3 h and stirred at room temperature for 16 h. The reaction mixture was cooled to 0° C. and quenched with water (1 mL) and 10% NaOH (1.5 mL) solution. The reaction mixture was stirred for 1 h. The solution was filtered through a pad of celite and rinsed with THF. The filtrate was concentrated and the resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 218 mg of quinolin-5-yl-methanol (48%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=C(C#N)[CH:28]=[N:29]C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:28]#[N:29])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: N#Cc1cncc(Br)c1
Product: Cc1ccc(Nc2cncc(C#N)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 5-Bromo-3-cyanopyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=334.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH3:14])=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23])[CH3:2].COC(=O)COC1C=CC(N(C(OC(C)(C)C)=O)C)=CC=1C(F)(F)F.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[C:22]([F:24])([F:25])[F:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NC)cc1C(F)(F)F

Procedure:
Analogously, to example 1.4, crude [4-(tert-butoxycarbonyl-methyl-amino)-2-trifluoromethyl-phenoxy]-acetic acid ethyl ester containing [4-(tert-Butoxycarbonyl-methyl-amino)-2-trifluoromethyl-phenoxy]-acetic acid methyl ester was deprotected with TFA to give (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester containing (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid methyl ester as light yellow waxy solid, MS: 278 (MH+) and 264 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccccc1CCl
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(chloromethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 207-208° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.6 Hz, 1H), 7.51-7.42 (m, 2H), 7.42-7.34 (m, 3H), 7.22-7.12 (m, 1H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.0 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.24-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 128.3 (q, J=30.8 Hz), 127.7, 126.8, 126.4 (q, J=5.8 Hz), 124.4 (q, J=273.7 Hz), 124.1, 123.8, 120.8, 111.5, 109.2, 99.5, 80.3, 64.5, 63.9, 58.2, 40.6; MS (ES+) m/z 454.1 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[C:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[NH:14][NH2:15]>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]([NH:15][NH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[O:12])=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Reactant: NNC(=O)OCc1ccccc1
Product: O=C(NNC(=O)c1ccnc2[nH]ccc12)OCc1ccccc1
Yield: 67 %

Procedure:
In the same manner as in Reference Example 1 and using 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of benzothiazole-6-carboxylic acid and benzyl carbazate instead of tert-butyl carbazate, the title compound (yield 67%) was obtained as pale-yellow crystals.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:19]([F:22])([F:21])[F:20])(=O)=O.[CH3:23][C:24]1[C:29]([CH3:30])=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:28]3[CH:27]=[CH:26][C:25]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:24]([CH3:23])[C:29]=3[CH3:30])=[C:8]([C:19]([F:22])([F:21])[F:20])[S:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(F)cc2)csc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(F)cc3)csc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-fluorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-fluoro-phenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 2H), 7.37 (s, 1H), 7.08 (t, J=8.0 Hz, 2H), 6.95 (d, J=7.0 Hz, 1H), 6.62 (d, J=7.0 Hz, 1H), 4.88 (s, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.22 (s, 3H), 2.08 (s, 3H).