Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3([CH2:25][C:26]#[N:27])[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.C([Sn](=O)CCCC)CCC.[N:38]([Si](C)(C)C)=[N+:39]=[N-:40]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([C:22]3([CH2:25][C:26]4[NH:40][N:39]=[N:38][N:27]=4)[CH2:23][CH2:24]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(-c2noc(C3(CC#N)CC3)c2-c2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCOc1ccc(-c2noc(C3(Cc4nnn[nH]4)CC3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of {1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropyl}-acetonitrile (the synthetic intermediate prepared in Example 42, Step A, 0.7 g) in toluene (10 mL) are added di-n-butyltin oxide (0.48 g) and azidotrimethylsilane (0.51 mL.) The stirring mixture is brought to reflux and continued stirring overnight. The mixture is subsequently cooled to room temperature, diluted with ethyl acetate (40 mL), and sequentially washed with water (20 mL) and brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with hexanes-ethyl acetate (1:1 v/v) and further elution with ethyl acetate afforded the synthetic intermediate 5-{1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl}-1H-tetrazole (0.6 g.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Br)c2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a light yellow amorphous solid. MS: 357.0 and 359.0 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:43]1([S:49]([N:52]2[C:56]3=[N:57][CH:58]=[C:59]([NH2:68])[C:60]([NH:61][CH:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)=[C:55]3[CH:54]=[CH:53]2)(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:68][C:59]1[C:60]([NH:61][CH:62]2[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)=[C:55]2[CH:54]=[CH:53][N:52]([S:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:51])=[O:50])[C:56]2=[N:57][CH:58]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)O
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
3-Acetylaminopropionic acid (0.089 g, 0.675 mmol), HATU (0.256 g, 0.675 mmol), and diisopropylethylamine (0.141 ml, 0.840 mmol) were added sequentially to a solution of 1-benzenesulfonyl-N-4-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.250 g, 0.675 mmol) in CH2Cl2 (15 ml) at 25° C. The reaction mixture was stirred for 18 h at 25° C., then was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×125 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc (10 ml) to give a solid which was collected by filtration, washed with Et2O (10 ml), and air-dried to give 3-acetylamino-N-(1-benzenesulfonyl-4-cyclohexylamino-1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide as an off-white solid (0.183 g, 56%). LCMS (Method G, ESI): RT=0.82 min, m+H=484.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3C(N)=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.N1C=CC=CC=1C.B.FC(F)(F)C(O)=O.[CH3:45][N:46]([CH3:49])[CH:47]=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:47]([N:46]([CH3:49])[CH3:45])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Reactant: CN(C)C=O
Agent: B
Agent: C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccn1
Product: CN(C)c1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (50 mg, 0.14 mmol) described in Example 1 and N,N-dimethylformamide (0.5 mL) were added a formaldehyde aqueous solution (34 mg, 0.42 mmol, content: 37%), α-picoline-borane (37 mg, 0.35 mmol), and acetic acid (50 μL), which was stirred overnight at the same temperature. Trifluoroacetic acid (50 μL) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The solvent was evaporated under a reduced pressure, and the residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (15 mg, 21%) as a trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:15]([CH2:14][CH2:13][CH2:12][CH2:11][Cl:10])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: Cc1ccc(N)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)CCCCCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml of pyridine, combined with 2.67 g (10.5 mmol) 75% m 4-chlorobutyl-sulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with 6-molar hydrochloric acid, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=9:1->7:3).
Reaction SMILES: NC1C=[N+]([O-])C=CC=1.C(CC(OCC)=O)(=O)C1C=CC=CC=1.C([O-])([O-])OCC.[C:29]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([C:46]=1[OH:47])=[N:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([C:37]1[CH:38]=[N:39][C:40]2[C:41]([C:46]=1[OH:47])=[CH:42][CH:43]=[N:44][CH:45]=2)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(c1ccccc1)c1cnc2cccnc2c1O
Agent: CCOC(=O)CC(=O)c1ccccc1
Agent: CCOC([O-])[O-]
Agent: Nc1ccc[n+]([O-])c1
Product: O=C(c1ccccc1)c1cnc2cnccc2c1O
Yield: 70 %

Procedure:
The 7-oxide of 3-benzoyl 4-hydroxy 1,7-naphthyridine is prepared from 3-aminopyridine 1-oxide described by J. C. Murray and C. R. Hauser in J. Org. Chem. p. 2008-14 (1954), ethyl benzoylacetate and ethyl orthoformate according to the process described for 3-benzoyl 4-hydroxy 1,5-naphthyridine; this product is obtained in 70% yield, m.p. >260° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[NH2:14][OH:15].Cl>CCO>[OH:15][NH:14][C:8](=[NH:9])[C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:1])([F:12])[F:13])=[CH:5][CH:6]=1
Reactant: NO
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: N=C(NO)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of 4-(trifluoromethoxy)benzonitrile (2.0 g, 10.6 mmol) in EtOH (20 mL), TEA (53 g, 53.0 mmol) and NH2OH.HCl (3.6 g, 26.5 mmol) were added in sequence. The mixture was refluxed for 4 h, cooled to RT, and concentrated under reduced pressure. The residue was diluted with H2O (20 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with H2O (1×10 mL) and brine (1×10 mL), dried over Na2SO4, filtered and concentrated to afford the crude N-hydroxy-4-(trifluoromethoxy)benzimidamide (2.0 g, 85%), which was directly used for next reaction without further purification. MS (ES+) C8H7F3N2O2 requires: 220, found: 221 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([CH2:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CNc1ccc(C(=O)O)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)CNc1ccc(C(=O)O)cn1

Procedure:
A 1.5 g portion of 6-methylaminonicotinic acid in 20 ml of acetic anhydride was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the residue was dissolved with saturated aqueous sodium bicarbonate, and the aqueous layer was washed with ethyl acetate and then adjusted to pH 3 using concentrated hydrochloric acid. Then the aqueous layer was extracted with chloroform, the organic layer was washed and dried, and then the solvent was evaporated under reduced pressure to obtain 280 mg of the title compound as white crystals.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:16]#[N:8])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.6 %

Procedure:
4-(Di-tert-butoxycarbonylaminomethyl)benzonitrile (2 g, 6.0 mmoles) (prepared as described in Preparative Example 247, Step A above) was dissolved in TFA (4 mL) and the solution was stirred at 25° C. for 0.25 h. The reaction mixture was diluted with dichloromethane and extracted with 1N sodium hydroxide. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (15×5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(aminomethyl)benzonitrile (108 mg, 68%): FABMS: m/z 133.1 (MH+); HRFABMS: m/z 133.0764 (MH+). Calcd. for C8H9N2: m/z 133.0766; δH (CDCl3) 2.04 (2H, s, —CH2NH2), 3.89 (2H, s, —CH2NH2), 7.40 (2H, d, Ar—H) and 7.59 ppm (2H, d, Ar—H); δC (CDCl3)CH2: 45.7; CH: 127.8, 127.8, 132.4, 132.4; C: 110.6, 118.9, 148.0.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[F:5][C:6]1([F:50])[CH2:11][CH2:10][CH:9]([C:12]2[C:21]3[CH:20]([OH:22])[CH2:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16]=3[N:15]=[C:14]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]4[N:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=4)[CH2:27][CH2:26]3)[C:13]=2[CH:38]([F:49])[C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH2:8][CH2:7]1>>[F:50][C:6]1([F:5])[CH2:7][CH2:8][CH:9]([C:12]2[C:21]3[CH:20]([OH:22])[CH2:19][C:18]([CH3:23])([CH3:24])[CH2:17][C:16]=3[N:15]=[C:14]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]4[N:36]=[CH:35][C:34]([O:37][CH:1]([CH3:3])[CH3:2])=[CH:33][N:32]=4)[CH2:29][CH2:30]3)[C:13]=2[CH:38]([F:49])[C:39]2[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CC(C)I
Product: CC(C)Oc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 13 were performed except for using isopropyl iodide instead of ethyl iodide and setting the reaction temperature to 50° C., and from 60 mg (90 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 54 mg of the title compound was obtained as a white solid (yield: 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=O)[NH:20][C:19]=1[CH3:26])=[O:17]>>[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:20][C:19]=1[CH3:26])=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2ccccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)NCCN(C)C

Procedure:
1,3-Dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:10][CH:9]=[CH:8][C:7]=1[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32]C)=[O:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[C:7]([O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OC
Yield: 92.4 %

Procedure:
A solution of 9.74 g (ca. 20 mmol) of rac-2-(4-ethoxy-4-oxobutoxy)-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, and 0.53 g of p-toluenesulfonic acid monohydrate, in 270 mL of methanol was stirred and refluxed for 21.5 hr. Most of the solvent was removed in vacuo and the residue was dissolved in ether. The ether solution was washed with saturated sodium bicarbonate solution and processed in the usual manner giving an oil. This material was chromatographed on 200 g of silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 7.03 g (92.5%) of 2-(6-hydroxyhexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])[CH:2]=[CH2:3].[CH:18](=[O:22])/C=C/C>>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[C:5](=[O:17])[CH:4]([CH2:1]/[CH:2]=[CH:3]/[CH:18]=[O:22])[CH2:12]2
Reactant: C=CCC1Cc2cc(OC)c(OC)cc2C1=O
Reactant: C/C=C/C=O
Product: COc1cc2c(cc1OC)C(=O)C(C/C=C/C=O)C2

Procedure:
The title compound 79 is prepared according to the procedure reported in step C of Example 8 with indanone 78 (0.5 g, 2.1 mmol) and crotonaldehyde (0.75 mL) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=1:1) afford the title compound 79 as a white solid. (Yield 0.5 g, 91%).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:20](OCC)=[O:21]>>[C:6]1([CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][CH2:3][C:2]([NH:1][CH:20]=[O:21])([CH3:19])[CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(N)COC(c1ccccc1)c1ccccc1
Reactant: CCOC=O
Product: CC(C)(COC(c1ccccc1)c1ccccc1)NC=O
Yield: 99.6 %

Procedure:
A mixture of 2-amino-1-diphenylmethoxy-2-methylpropane (7.6 g -- see Preparation 1) and ethyl formate (6.7 g) was heated at 100° in a steel bomb for 18 hours and evaporated. The residue was purified by chromatography on silica (18 g) using hexane plus 0-100% methylene chloride as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless gum (8.4 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1I.C([O-])(=O)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:36][C:37]([F:41])([F:40])[CH:38]=[CH2:39]>CN(C)C=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH:39]=[CH:38][C:37]([F:41])([F:40])[F:36]
Reactant: C=CC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(I)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=CC(F)(F)F)c(Cl)c1

Procedure:
2.85 g of 3-chloro-4-iodo-nitro-benzene, 0.95 g of sodium acetate, 0.0048 g of Pd(OAc)2, 0.048 g of triphenylphosphine and 2 g of 3,3,3-trifluoro-propene were reacted in 25 ml of dimethylformamide at 130° C. for 24 h, under stirring. The reaction mixture was cooled, breathered to atmospheric pressure, poured in water and extracted with ethyl ether (5×80 ml). The organic extract was anhydrified on Na2SO4 and purified by chromatography on silica gel column (hexane 95%--ethyl-acetate 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=O.B>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([CH2:7][NH:9][CH:10]2[CH2:11][CH2:12]2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1C(=O)NC1CC1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1CNC1CC1
Temperature: 25 °C

Procedure:
At 0° C., a suspension of 5-chloro-N-cyclopropyl-2-methylbenzamide (1 eq.) from the previous step in THF (0.4 M) was added borane (1.0 M in THF, 3 eq.). The resulting suspension was warmed to RT over 1 h and then heated at reflux for 1 h. The now pale yellow solution was re-cooled to 0° C. and carefully quenched with 1 N aq. HCl. The resulting mixture was heated at reflux for 1 h to ensure complete breakdown of the amine-borane complex. Following careful neutralization with 1 N aq. NaOH, the aqueous layer was separated and back extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product thus obtained was purified further by way of flash chromatography (SiO2, Hex→4:1 (v/v) Hex:Et2O) to reveal the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][N:7]=1)#[N:2].CN(C=O)C.C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl>[Cl:31][C:6]1[N:7]=[C:3]([C:1]#[N:2])[NH:4][C:5]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C#N)[nH]2)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C#N)nc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.3, 290 mg, 1.20 mmol) in a solvent mixture of DMF and CHCl3 (4/20 mL). NCS (161 mg, 1.21 mmol, 1.00 equiv) was added to the above reaction mixture. The reaction mixture was stirred overnight at room temperature, then was concentrated under reduced pressure. The residue was diluted with 30 mL of EtOAc, then was washed with 3×15 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/10-1/7) as eluent to furnish 160 mg (48%) of the title compound as light yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1>CS(C)=O>[N:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[S:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:8]=1
Reactant: ClCc1ccncc1
Reactant: c1ccc2c(c1)Sc1ccccc1C2Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)Sc1ccccc1C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A quantity of 0.38 g (8.0 mmole) of 50% sodium hydride oil dispersion was added slowly during 15 minutes to 20 ml of dimethyl sulfoxide at room temperature. After completion of addition, the reaction mixture was heated at 45° for 30 minutes. It was cooled to 15° and a solution of 2.3 g (8.0 mmole) of 9-(4-pyridinylmethyl)thioxanthene in 10 ml of dimethylsulfoxide was added dropwise during 15 minutes at room temperature. After completion of addition, the reaction mixture was stirred 30 minutes at room temperature. Then a solution of 4-picolylchloride (8.75 mmole) in 5 ml of dimethylsulfoxide was added dropwise during 30 minutes at ambient temperature. The reaction was then heated at 40° for 30 minutes. The reaction was quenched by addition of water (50 ml). Trituration of the precipitated oil yielded a crystalline solid, which was filtered off, washed with water and dried. The tan solid was dissolved in benzene and decolorized by stirring with 1 g of Magnesol® for 30 minutes. Filtration and evaporation yielded a colorless product (2.0 g) which was recrystallized from ethylacetate, m.p., 201.4-203.4°.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[C:16]=3[N:15]=[C:14]([NH2:26])[N:13]=2)(=O)=O)=CC=1.Cl.Cl.[NH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=1>>[NH2:39][C:35]1[N:34]=[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4([CH2:22][CH2:23][CH2:24][CH2:25]4)[C:16]=3[N:15]=[C:14]([NH2:26])[N:13]=2)[CH:38]=[CH:37][N:36]=1
Reactant: NCCNc1ccnc(N)n1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Agent: Cl
Product: Nc1nccc(NCCNc2nc(N)nc3c2CCCC32CCCC2)n1

Procedure:
The product from Example 10D (61 mg, 0.163 mmol) and the product from Example 1E (44 mg, 0.195 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (dd, J=11.19, 5.43 Hz, 2H) 1.47-1.57 (m, 2H) 1.57-1.69 (m, 4H) 1.69-1.83 (m, 2H) 1.96-2.09 (m, 2H) 2.16 (t, J=5.93 Hz, 2H) 3.33-3.52 (m, 4H) 5.45 (s, 2H) 5.66-5.77 (m, 1H) 5.84 (s, 2H) 6.20 (s, 1H) 6.89 (s, 1H) 7.61 (d, J=5.09 Hz, 1H); MS (ESI+) m/z 355.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:44]([NH:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:45])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccccc4)c(F)c3)ccnc2cc1OCc1ccccc1

Procedure:
After adding 1.90 g of the 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained in Production Example 8 to 60 ml of toluene and 30 ml of acetonitrile, the mixture was heated to reflux. Next, 0.76 ml of phenyl isocyanate was added and the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and dried under reduced pressure to obtain 1.65 g of the title compound.