Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C([O:10][C:11](=[O:44])[CH2:12][O:13][C:14]1[C:19]([I:20])=[CH:18][C:17]([C:21](=[O:42])[C:22]2[CH:27]=[C:26]([I:28])[C:25]([O:29][CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])=[C:24]([I:41])[CH:23]=2)=[CH:16][C:15]=1[I:43])C1C=CC=CC=1.Cl>C1COCC1>[C:11]([CH2:12][O:13][C:14]1[C:15]([I:43])=[CH:16][C:17]([C:21]([C:22]2[CH:23]=[C:24]([I:41])[C:25]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:26]([I:28])[CH:27]=2)=[O:42])=[CH:18][C:19]=1[I:20])([OH:44])=[O:10]
Reactant: O=C(COc1c(I)cc(C(=O)c2cc(I)c(OCC(=O)OCc3ccccc3)c(I)c2)cc1I)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1c(I)cc(C(=O)c2cc(I)c(OCC(=O)O)c(I)c2)cc1I
Reaction time: 48 h
Yield: 83.1 %

Procedure:
A 1.2 M solution of lithium hydroxide (300 μL, 0.36 mmol) was added to a solution of [4-(4-benzyloxycarbonylmethoxy-3,5-diiodo-benzoyl)-2,6-diiodo-phenoxy]-acetic acid benzyl ester (prepared according to Example 12, 76 mg, 0.075 mmol) in 2.4 mL THF. The suspension was stirred for 48 hours, after which time the mixture was poured into 1 M HCl. The resulting white precipitate was isolated by filtration, rinsed with water, and dried in vacuo, yielding the title compound as a white powder (52 mg, 83%). 1H NMR (400 MHz, DMSO-d6): δ 13.17 (br. s, 2H), 8.09 (s, 4H), 4.55 (s, 4H). HPLC (40-90), 10.29 min. LRMS (EI−) calc'd for [C17H10I4O7—H] 832.7, found 832.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.Cl.[CH3:20][N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.C(OC(O)C)C>N1C=CC=CC=1>[CH3:20][N:21]([CH3:29])[C:22]1[CH:23]=[C:24]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(OC)c2c(Nc3cccc(N(C)C)c3)c(C#N)cnc12
Yield: 77.2 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.146 g of N,N-dimethyl-1,3-phenylenediamine dihydrochloride, 0.2 ml of pyridine, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. Then the mixture was partitioned between ethyl acetate and saturated sodium chloride solution. The organic layer was dried and concentrated in vacuo. The residue thus obtained was chromatographed on silica gel eluting with ethyl acetate. Solvent was removed from product fractions giving 0.160 g of 4-(3-dimethylamino-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 103-105° C.; mass spectrum (EI, m/e): M 348.1588.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[Se:18][C:17]=1[C:25]([NH2:27])=[O:26].CN(C=O)C.[OH-].[Na+]>>[C:11]([C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:15][C:16]3[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[Se:18][C:17]=3[C:25]([NH2:27])=[O:26])[C:3]=2[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: CC(C)(C)c1cc2c(Cl)ncnc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(Nc3cc(C(C)(C)C)[se]c3C(N)=O)ncnc2o1

Procedure:
The reaction of 4-chloro-6-tert-butylfuro[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as an off-white color solid, mp 288-290° C. IR (KBr) vmax 3491, 3325 2964, 1593, 1388, 1354, 1314, 1287, 1149, 1119, 1089, 936, 806, 773 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.80 (1H, s, exchangeable with D2O), 8.46 (2H, s), 7.48 (2H, br s, exchangeable with D2O), 6.41 (1H, s), 1.39 (9H, s), 1.36 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 167.1, 166.0, 164.1, 152.6, 152.3, 144.9, 121.0, 113.1, 103.3, 94.8, 36.4, 32.7, 32.2, 28.23; LC-MS (negative ion mode): m/z 417, 419 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[N:12][CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1.CC(C)([O-])C.[Na+].COCCOC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:26]1([NH:1][C:2]2[CH:3]=[C:4]([C:10]3[N:15]=[C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH:13]=[N:12][CH:11]=3)[CH:5]=[N:6][C:7]=2[O:8][CH3:9])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1ncc(-c2cncc(CNC(=O)OC(C)(C)C)n2)cc1N
Reactant: Clc1nccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ncc(-c2cncc(CNC(=O)OC(C)(C)C)n2)cc1Nc1nccc2ccccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
tert-butyl 6-(5-amino-6-methoxypyridin-3-yl)pyrazin-2-ylmethylcarbamate (100 mg, 0.30 mmol, 1 eq.), 1-chloroisoquinoline (59 mg, 0.36 mmol, 1.2 eq.), Pd(OAc)2 (6.8 mg, 30.2 μmol, 0.1 eq.), Josiphos (16.7 mg, 30.2 μmol, 0.1 eq.) and sodium tert-butoxide (41 mg, 0.42 mmol, 1.4 eq.) were placed in a 2.5 mL V-bottomed Wheaton vial and dry DME (0.5 mL) was added. The resulting mixture was stirred at 90° C. overnight. The reaction mixture was allowed to cool to RT, diluted with DCM, silica (10 mL) added, concentrated under reduced pressure and purified by column chromatography (50% EtOAc in hexanes, dry loaded on silica, 100 mL silica) to give an ochre foam (76.6 mg, 56% Yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])(=[O:3])C.Br[O-].[Na+].S(=O)(O)[O-:30].[Na+]>O1CCCC1>[CH3:10][C:9]1[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[C:1]([OH:30])=[O:3]
Reactant: O=S([O-])O
Reactant: CC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [O-]Br
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.5 g), tetrahydrofuran (70 ml), sodium hypobromite (70 ml) was stirred for 2 hours at ambient temperature. To the mixture was added an aqueous sodium bisulfite solution. The mixture was washed with diethyl ether (100 ml) and the aqueous solution was acidified to pH 3.0 with 10% hydrochloric acid. The resultant crystals were collected by filtration to give 0.80 g of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1([Cl:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:14].[Cl:16]N(Cl)C(OCC)=O>CC(O)=O>[Cl:15][C:2]1([Cl:1])[C:10]2[C:5](=[C:6]([Cl:16])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:14]
Reactant: COc1ccc2c(c1Cl)C(Cl)(Cl)C(=O)N2
Reactant: CCOC(=O)N(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(Cl)c2c(c1Cl)C(Cl)(Cl)C(=O)N2
Temperature: 60 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
11.54 g of 3,3,4-trichloro-5-methoxy-1 ,3-dihydro-indol-2-one (43.3 mmol) was suspended in glacial AcOH (200 mL). 3.343 g (21.7 mmol) of N,N-dichlorourethane was added and the mixture was stirred at 60° C. for 2 days. The reaction mixture was cooled to room temperature, the precipitate collected by filtration and dried on high vacuum. Re-crystallization from benzene (150 mL) yielded 6.135 g of product (containing 5% of the start. material as an impurity).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:15])=[O:4].[OH:16][CH:17]([CH:19](O)[CH3:20])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:15])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][Cl:1])[O:16][CH:17]([CH3:18])[CH:19]([CH3:20])[O:14]1
Reactant: CC(O)C(C)O
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cccc(C2(C)OC(C)C(C)O2)c1NC(=O)CCl

Procedure:
The product from Example 1 (10.6 g), 2,3-dihydroxybutane (8.5 g) and p-toluene sulfonic acid (1.5 g) in 200 ml benzene were refluxed to 2 hours, removing water with a Dean-Stark trap. The solution wash washed with 10% NaOH, dried (MgSO4) and stripped. The product was chromatographed on a silica gel column, eluting with 30% ether-hexane. Yield: 3.8 g of the title product, mp 55°-57° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([C:21]1[CH:20]=[C:19]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:18]([OH:27])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:22]=1)=[O:5]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cc1cc(C)c(C(=O)Cl)c(Cl)n1
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Yield: 81.9 %

Procedure:
The similar procedure in reference example 1 by using 12.2 g of 2-chloro-4,6-dimethylnicotinoyl chloride, 14.8 g of 2,6-di-tertiary butylphenol and 18.8 g of anhydrous stannic chloride in dichloroethane is performed and the obtained crude product is recrystallized from hexane to give 18.3 g of 4-(2-chloro-4,6-dimethylnicotinoyl)-2,6-di-tertiary butylphenol as pale yellow crystals, melting at 129°-132° C. According to the similar manner as the above Reference Examples, 4-(2-chloro-6-isopropylnicotinoyl)-2,6-di-tertiary butylphenol, melting at 109°-110° C. is prepared.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:13]2=[O:24])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][CH:33](Br)[CH2:34][CH3:35]>C(#N)CC>[CH:33]([O:23][C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH:15]=[CH:16][N:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:25])[CH3:1])=[CH:11][CH:10]=3)[C:13]2=[O:24])=[CH:22][CH:21]=1)([CH2:34][CH3:35])[CH3:32]
Reactant: CN(C)CCOc1ccc(-n2ccn(-c3ccc(O)cc3)c2=O)cc1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC#N
Product: CCC(C)Oc1ccc(-n2ccn(-c3ccc(OCCN(C)C)cc3)c2=O)cc1
Temperature: 80 °C

Procedure:
A solution of 1-[4-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in propionitrile (1 mL) was mixed with cesium carbonate (100 mg) and 2-butyl bromide (25 mg) and heated at 80° C. for 2 hours. The reaction solution was filtered and the concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 395.51 (C23H29N3O3); MS (ESI): 396 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CCCCOc1cc(F)ccc1B(O)O
Product: CCCCOc1cc(F)ccc1-c1c(-c2cc(C#N)ccn2)ncn1C

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 2-butoxy-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H19FN4O, 351. Found, 351.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>O1CCCC1.Cl.C(OC(C)C)(C)C>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)=[CH:26][C:19]=1[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])#[N:22]
Reactant: Cc1ccccc1C(O)CCC(=O)[O-]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of sodium 4-hydroxy-4-(2-methyl-phenyl)butanoate, thought to be the (R)-enantiomer, (3 g) and sodium hydride (1.5 g; 60% w/v dispersion in mineral oil; 37.5 mmol) in tetrahydrofuran (50 mL) is stirred at ambient temperature for 1 hour under an atmosphere of argon, and is then warmed to 55° C. It is then treated with 2-fluoro-4-(3-thienylmethoxy)benzonitrile (3 g), in one portion, and stirring is continued at 55° C. for 15 hours. The mixture is then cooled, diluted with hydrochloric acid (200 mL; 1 N) and extracted with ethyl acetate (4×100 mL). The combined extracts are dried over magnesium sulphate and concentrated in vacuo, to give an oily residue. This residue is boiled in isopropyl ether, and the resulting mixture is filtered while hot, and then allowed to cool. The yellow solid which separates is collected and recrystallized from a mixture of ethyl acetate and hexane, to give 4-[2-cyano-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (1.5 g) in the form of a white fluffy solid, m.p. 145° C. Chiral HPLC assay showed a 98% enantiomeric excess. [Elemental analysis:- C,67.82;H,5.18; N,3.24%; Calculated:- C,67.80;H,5.19;N,3.44%].
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na].[CH2:21]1O[CH2:22]1>COCCOCCOC>[CH2:1]([S:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: C1CO1
Agent: [Na]
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCCCCCCCSCCCCCCCCCCCCCCCCCC
Yield: 65 %

Procedure:
1-Octadecanethiol, 250 g. (0.87 mole), was dissolved in 250 ml of bis-(2-methoxyethyl) ether. Three grams (0.13 mole) of cut sodium spheres were added and the reaction mixture was transferred to a rocking autoclave and ~462 g. of ethylene oxide was bled into the autoclave over a period of 3 hours at 140°-160° C. The maximum pressure observed was 540 lbs. After all the ethylene oxide had been added, rocking was continued for an additional hour. The mixture was cooled, the bis-(2-methoxyethyl) ether was evaporated under reduced pressure, and the residue crystallized from hexane to give a white solid in 65% yield based on the octadecane thiol.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:6]=2[C:19]=1[CH3:20].[C:23]1([C@H:29]([NH2:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:23]1([C@H:29]([NH:31][C:2]2[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]3[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[C:6]=3[C:19]=2[CH3:20])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C2c3c(C)c(Br)c(C)c(C)c3OC2(C)C)cc1
Reactant: C[C@@H](N)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3c(C)c(N[C@H](C)c4ccccc4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 107 °C
Reaction time: 7 h
Yield: 95.3 %

Procedure:
Under a nitrogen atmosphere, to toluene (10 mL) were added 5-bromo-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (2 g) and (R)-(+)-1-phenylethylamine (0.94 g), then palladium acetate (5 mg) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-dinaphthyl (41.6 mg), and further sodium tert-botoxide (0.86 g). The mixture was stirred at 107° C. for 7 hours. Diluted hydrochloric acid was added to the reaction solution. The organic layer was separated and washed with a 10% aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which was eluted with ethyl acetate-n-hexane [1:9], to obtain the title compound (2.12 g, 95.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([O:14]C)=[N:10][CH:11]=[CH:12][CH:13]=1>Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:14])[NH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ncccc1-c1ccc(NC(=O)Nc2ccccc2C)cc1F
Agent: Cl
Product: Cc1ccccc1NC(=O)Nc1ccc(-c2ccc[nH]c2=O)c(F)c1

Procedure:
1-[3-Fluoro-4-(2-methoxypyridin-3-yl)phenyl]-3-o-tolylurea (P12) (0.150 g, 0.43 mmol) in ethanolic hydrochloric acid (10 mL) was stirred at reflux for 8 hours. The reaction mixture was then allowed to cool, and concentrated to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1N

Procedure:
Prepared from (3′-fluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B11) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a brown solid (3.40 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:22][C:14]1[CH:13]=[C:12]([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(COc2ccc(C=O)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
p-Hydroxybenzaldehyde (3.18 g, 26.1 mmol), 4-chloromethyl-2-methyl-quinoline (5.0 g, 26.1 mmol), and potassium carbonate (7.2 g, 52 mmol) were combined in acetonitrile (100 mL) and heated to reflux overnight. The reaction was allowed to cool to room temperature, diluted with ethyl acetate, filtered to remove the solids, and concentrated to give a semi-solid residue. The crude product was crystallized from ethyl ether to give 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde (6.5 g, 90%) as an off white precipitate. MS found: (M+H)+=278.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of diphenylacetonitrile (1-g) in tetrahydrofuran (10 ml) was added 60% sodium hydride (0.25 g) in small portions under ice-cooling. After completion of dropwise addition, the mixture was stirred for 20 minutes. Then, ethyl 4-bromobutyrate (0.94 ml) was added dropwise under ice-cooling and the mixture was further stirred at room temperature for 15 minutes. This reaction mixture was poured into ice-water and the organic layer that had separated out was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (0.87 g) as colorless oil.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]1[OH:10])=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][OH:23].C(OC(N[C@@H]1CCN(CCO)C[C@@H]1C(OC)=O)=O)C1C=CC=CC=1>>[N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:21][CH2:22][OH:23])[CH2:6][C@H:5]1[OH:10])=[N+:2]=[N-:3]
Reactant: OCCBr
Reactant: [N-]=[N+]=N[C@H]1CCNC[C@H]1O
Agent: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=N[C@H]1CCN(CCO)C[C@H]1O
Yield: 93 %

Procedure:
Cis(±)4-azidopiperidin-3-ol (prepared following the procedure described in WO 2005/066176 for the chiral material) (0.945 g, 6.65 mmol), N,N-diisopropylethylamine (1.7 mL, 10 mmol) and 2-bromoethanol (0.61 mL, 8.64 mmol) were reacted as described for Intermediate 37, except heating for one hour. The solvent was removed under reduced pressure. The residue was taken up in dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL) and the aqueous phase was back extracted five times with dichloromethane (5×100 mL). The combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol 3:1 gave 1.15 g (93%) of the product as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:14]([CH:15]([CH3:17])[CH3:16])[C:9]3=[N:8][C:7]=2[CH:25]=1.CCN(CC)CC.[C:37](Cl)([CH3:39])=[O:38].CCOC(C)=O>C(Cl)Cl>[C:37]([O:1][CH2:2][C:3]1[C:4]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:25]=1)(=[O:38])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a 50 mL round-bottomed flask containing (R)-tert-butyl 8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (236 mg, 0.558 mmol) in CH2Cl2 (5 mL) was added Et3N (169 mg, 1.67 mmol) and AcCl (87 mg, 1.12 mmol) under N2. The mixture was stirred at rt for 10 min. The reaction was quenched with water (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with water (25 mL) and brine, and then dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1-4:1 to give (R)-tert-butyl 8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (210 mg, 81.1% yield) as a yellow solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[S:59][C:60]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)=[CH:61][N:62]=4)=[O:57])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56]([C:58]4[S:59][C:60]([C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=5)=[CH:61][N:62]=4)=[O:57])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 612 was prepared analogous to compound of example 98 by hydrolysis of compound of example 611.