Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([CH2:14][CH2:15][NH2:16])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>C(O)(=O)C>[C:1]1(=[O:6])[N:16]([CH2:15][CH2:14][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of maleic anhydride (0.05 mole) in acetic acid (20 mL) was mixed with a solution of ε-Amino-n-caproic acid (0.05 mole) in acetic acid (50 mL) and stirred at room temperature for 2 hours. An additional amount of acetic acid (150 mL) was added and the reaction mixture refluxed for 16 hours. The reaction mixture was evaporated under vacuo to an oil and chloroform was then added (50 mL). The solution was left to stand for 16 hours at room temperature whereupon impurities were precipitated out of the solution. The precipitate was filtered and the filtrate was collected, evaporated under vacuo and chromatographed on silica gel using chloroform:acetic acid (95:5) to give 6-Maleimidocaproic acid 23 (8 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH3:17])[C:7]2=[O:18].[CH3:19][C@@H:20]1[C:24]2[NH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:23]=2[C:22](=[O:37])[NH:21]1>>[CH3:17][N:8]1[C:7](=[O:18])[C:6]2[C:11](=[C:2]([C:26]3[NH:25][C:24]4[C@@H:20]([CH3:19])[NH:21][C:22](=[O:37])[C:23]=4[CH:27]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC2(C)CC2)nc2c(I)cccc2c1=O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC5(C)CC5)nc34)[nH]c21
Yield: 52 %

Procedure:
This compound (85 mg, 52% yield) as a brown solid was prepared according to the procedure described for Example 448, using 8-iodo-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (713) (160 mg, 0.45 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (130 mg, 0.50 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (1H, br.), 8.13 (1H, dd, J=7.6, 1.4 Hz), 7.83 (1H, dd, J=7.8, 1.4 Hz), 7.69 (2H, d, J=3.1 Hz), 7.18 (1H, t, J=7.7 Hz), 6.96 (1H, s), 4.64 (1H, q, J=6.6 Hz), 3.40 (3H, s), 1.56 (3H, s), 1.37 (3H, d, J=6.7 Hz), 1.01 (2H, m), 0.86 (2H, m). MS (ESI, pos. ion) m/z: 364.0 (M+1).
Reaction SMILES: C(OC([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[O:27]1
Reactant: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1)C(=O)OC(C)(C)C)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A stirred solution of methyl 2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 82, 61 mg, 0.096 mmol) in MeOH (0.50 mL) was treated with HCl in dioxane (1 mL of a 4N solution in dioxane, Aldrich Chemical Co.) at room temperature and stirring continued for 60 minutes. The mixture was concentrated in vacuo and purified on silica gel using a gradient of 5-10% MeOH/EtOAc to provide 31 mg of product as colorless oil (77%); 1H NMR (DMSO-d6, δ): 1.65-2.04 (m, 2 H), 2.50-3.10 (m, 6 H), 3.65 (s, 3 H), 4.10 (dd, 1 H), 4.80 (d, 1 H), 6.80 (d, 1 H), 7.00 (bs, 2 H), 7.25-7.40 (m, 3 H), 7.42-7.52 (m, 1 H), 7.78-7.80 (m, 2 H), 8.52 (s, 1 H), 8.60 (s, 1 H); MS: m/z=419.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:22]([NH2:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]([CH2:15][CH3:16])[C:12]([NH:24][CH2:22][CH3:23])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCN
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1
Product: CCNC(=O)C(CC)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using 2-[(3-chloro-4-cyanophenyl)(2,2,2-trifluoroethyl)amino]butanoic acid and ethylamine: MS (ES) m/z 348 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An amount of 305 mg (0.99 mmol) of the compound from Example 19A and 355 mg (1.09 mmol) of caesium carbonate were suspended in 10 ml of acetone and admixed with 227 mg (0.99 mmol) of methyl 4-(bromomethyl)benzoate. The mixture was stirred at 50° C. for 3 h. The suspension was diluted with water. It was extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 10:1→2:1) gave 284 mg (63% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:12](=[O:11])[CH3:17]
Reactant: COc1ccccc1C=CC(C)=O
Reactant: O=Cc1ccccc1Br
Product: CC(=O)C=Cc1ccccc1Br

Procedure:
The title compound was prepared from 2-bromo-benzaldehyde (30 g, 162 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 5-chloro-2-methoxyphenylsulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 5-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-methoxy-benzenesulfonamide as a colorless oil. MS: 544.8 ([M+NH4]+)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid. LC-MS-conditions 01: tR=0.92 min; [M+H]+=370.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=O)[CH2:23][CH2:24][C:25]4[N:26]=[CH:27][NH:28][CH:29]=4)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]4[N:26]=[CH:27][NH:28][CH:29]=4)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: O=C(CCc1c[nH]cn1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCN(CCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of compound (16) (0.65 g; 1.5 mmol) in anhydrous tetrahydrofuran (70 ml) was added a 1.0M solution of lithium aluminum hydride in tetrahydrofuran (4.6 ml; 4.6 mmol). The mixture was stirred at room temperature for 1.75 h. then diluted with ethyl ether and quenched with dropwise addition of saturated ammonium chloride solution. To saturated ammonium chloride
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([OH:14])=O)=[CH:8][NH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:14])=[CH:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1c[nH]c2nc(Cl)ccc2c1=O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1c[nH]c2nc(Cl)ccc2c1=O

Procedure:
7-Chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, (1 g) and N,N'-carbonyldiimidazole (1.1g) in dimethylformamide (12 ml) were heated at 100° for 1 hour. 5-Amino-1H-tetrazole (0.95 g) was added and the mixture was heated at 100° for 1 hour and cooled. The solid was filtered off and stirred with aqueous hydrochloric acid (10 ml, 2N) and the solid was collected and dried, m.p. above 350°.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:11])=[O:10]
Reactant: N#CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (0.41 g, 4.2 mmol) in methylene chloride (10 mL) was added methanesulfonyl chloride (490 uL, 6.3 mmol), followed by triethylamine (1.5 mL, 10.0 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield the crude product which was used in the next step reaction without further purification.
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=1)[C:35]([OH:37])=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2-chloro-6-trifluoromethyl-isonicotinic acid (prepared in analogy to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) after a reaction time of 18 hours. The compound was purified by two silica gel chromatographies on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (26%). MS (ESI): m/z=440.08 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:25])[CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]([OH:25])[CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(C=CCC(=O)CCCCCOCc2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(C=CC[C@H](O)CCCCCOCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a solution of 11-3 (4.0 g, 12.3 mmol) in methanol (150 mL) at −15° C. was added sodium borohydride (0.515 g, 13 mmol). After 10 minutes, conc. HCl was added until bubbling ceased, and then sat. NaHCO3 was added to reach pH=10. The mixture was warmed to room temperature, the methanol removed, and the residue diluted with ethyl acetate, washed with sat. NaHCO3 and brine, and dried over magnesium sulfate. Evaporation of the solvents gave a residue which was purified on a 10×50 cm Chiralpak AD column (flow=200 ml/min, A:B=20:80) (A=0.1% diethylamine/hexane, B=ethanol). Product 11-4 elutes at 21 minutes, providing 1.7 g of 11-4 (84% yield of theoretical); its enantiomer elutes at 45 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 88 %

Procedure:
12 drops of dimethylformamide was added to a solution of 3.0 g (18.9 mmol) of 2-chloropyrimidine-4-carboxylic acid in 60 ml of thionyl chloride. The reaction was then refluxed for 6 hours. After cooling to room temperature, excess thionyl chloride was removed on a rotary evaporator and the residue distilled (boiling point approximately 100° C./1 mbar). 2.95 g of product, corresponding to a yield of 88 percent relative to the 2-chloropyrimidine-4-carboxylic acid used, which crystallized in the receiving flask, was obtained. The melting point of the product was 52.2° to 53.1° C. Other data for the product was:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 65 °C
Yield: 98.6 %

Procedure:
To a mixture of 4-bromo-3,5-dimethyl-phenol (40.2 g, 0.200 mol) and potassium carbonate (55.2 g, 0.400 mol) in acetone (200 mL) was added methyl iodide (24.9 mL, 0.600 mol) at room temperature under N2. The reaction mixture was then refluxed at 65° C. for 8 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The resulting clear liquid was distilled under reduced pressure (70° C./0.1 Torr) to give 42.4 g (99%) of title compound as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.663 (s, 2H), 3.778 (s, 3H), 2.402 (s, 61-1); 13C NMR (100 MHz, CDCl3): δ 158.165, 139.203, 118.357, 113.953, 55.520, 24.319. MS (EI): m/z 214 [M+, 79Br 100], 216 [M+, 79Br, 96].
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[CH:14][C:6]1[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=1[CH:4]=2.[Br:19]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[C:3]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[CH:14][C:6]1[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=1[CH:4]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2cc3c(cc12)oc1ccccc13
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2cc3c(cc12)oc1ccccc13
Yield: 101 %

Procedure:
To a RB flask was added 7-methyl-benzo[b]naphtho-[2,3-d]furan (Cambridge Chemicals, Inc., 16.0 g, 0.07 mol), N-bromosuccinimide (Aldrich 12.8 g, 0.072 mol, recrystallized from H2O and dried under high vacuum overnight), a catalytic amount of benzoyl peroxide (0.01 g) and CCl4 (1 L). The mixture was refluxed for 2.5 h, cooled and filtered to remove the succinimide formed in the reaction. The solvent was then removed from the reaction mixture by rotary evaporation. The crude product was purified by flush chromatography on SiO2 using PhCH3 as the eluting solvent. The appropriate fractions were combined and the solvent once again removed by rotary evaporation to give 22.0 g of product. The material (which was one spot by TLC and pure by NMR) was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(N(CC)CC)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCc1ccccn1
Reactant: O=C(NCc1ccc(O)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(OCc2ccccn2)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 100 mg (0.25 mmol.) 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide [Prepared analogous to preparation 35 by substituting 2-chloro-5-fluoro-nicotinic acid (EP 0634413 A1)], 10 mL DMF and 175 mg (1.25 mmol.) potassium carbonate was added a solution of DMF (5 mL) containing 82 mg (0.5 mmol.) 2-chloromethyl-pyridine hydrochloride (Aldrich) and 1 equivalent of triethyl amine. The resulting mixture was stirred for 3 days at room temperature. Reaction mixture was poured into ice water (200 mL) and the resulting solid was filtered, washed with cold water and dried in vacuo to afford desired product.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:21]1[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1)([O-])=O>O1CCCC1>[F:14][C:12]([F:15])([F:13])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:21]3[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: FC(F)(F)Oc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(OC(F)(F)F)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A solution of 2-mercapto-5-trifluoromethoxy-benzimidazole (1.26 g, 5.38 mmol) in tetrahydrofuran (10 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.344 g, 8.61 mmol) and tetrahydrofuran (5 ml) at 0° C. The mixture is stirred at room temperature for 2 hours. A solution of 5-nitro-2-furaldehyde (0.76 g, 5.38 mmol) in tetrahydrofuran (15 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 10 ml of dichloromethane and filtered through a silica gel plug (40 ml). The silica gel plug is eluted with 800 ml of cylohexane/ethyl acetate (7/3, v/v). The organic filtrates are combined and concentrated under reduced pressure to yield 1.1 g of 5-(5-trifluoromethoxy-1H-benzoimidazol-2-ylsulfanyl)-furan-2-carbaldehyde as an oil. Yield=62%. Analytical LC/MS (method B): retention time=3.77 min., m/z=329.0 (positive ion mode).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:15]2=[O:27])[CH:8]=1>O1CCCC1>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([O:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:28])=[O:5])[C:15]2=[O:27])=[CH:24][CH:23]=1)#[N:26]
Reactant: COC(=O)c1cccc(O[C@@H]2CCN(c3ccc(C#N)cc3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N2CC[C@@H](Oc3cccc(C(=O)O)c3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Add water (2 mL) followed by lithium hydroxide (0.62 g, 14.9 mmol) to a solution of 3-[(R)-1-(4-cyano-phenyl)-2-oxo-pyrrolidin-3-yloxy]-benzoic acid methyl ester (1.00 g, 2.98 mmol) of in tetrahydrofuran (4 mL). Stir the mixture overnight at room temperature then concentrate under reduced pressure to remove volatile organics. Wash the concentrated aqueous mixture with EtOAc and then acidify to pH 4 using a 0.5 M solution of citric acid. Extract the mixture with EtOAc and concentrate under reduced pressure to provide 0.74 g of 3-[(R)-1-(4-cyano-phenyl)-2-oxo-pyrrolidin-3-yloxy]-benzoic acid as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[N:15]=[C:14]3Cl)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[Se:28][C:27]=1[C:35]([NH2:37])=[O:36].CN(C=O)C.[OH-].[Na+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[N:15]=[C:14]3[NH:25][C:26]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:32])[CH3:33])[Se:28][C:27]=2[C:35]([NH2:37])=[O:36])[CH2:3][CH2:2]1
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OCCCN1CCOCC1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 6-(3-morpholinopropoxy)-4-chloro-7-methoxy-2-methylquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a brown color solid, mp 204-206° C. 1H NMR (400 MHz, CDCl3): δ 11.92 (1H, br s), 8.95 (1H, s), 7.34 (1H, s), 7.18 (1H, s), 5.37 (2H, br s), 4.29 (2H, t, J=6.0 Hz), 3.98 (3H, s), 3.73 (4H, t, J=4.4 Hz), 2.70 (3H, s), 2.61 (2H, t, J=7.2 Hz), 2.50 (4H, br s), 2.11-2.14 (2H, m), 1.47 (9H, s); LC-MS (positive ion mode): m/z 560, 562 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:38])([F:37])[CH2:19][N:20]1[C:24]([CH2:25]O)=[CH:23][C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:21]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][C:24]3[N:20]([CH2:19][C:18]([F:37])([F:17])[F:38])[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless oil.