Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[OH:67]>ClCCl.CO>[Br:1][C:65]1[CH:64]=[CH:63][C:62]([OH:67])=[C:61]([O:60][CH2:59][CH2:58][CH2:57][O:56][CH3:55])[CH:66]=1
Reactant: [Br-]
Reactant: COCCCOc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(Br)ccc1O
Reaction time: 0.5 h

Procedure:
6.9 g of tetrabutylammonium tribromide are added in portions, at room temperature, to a solution of 2.6 g of 2-(3-methoxypropyloxy)-phenol in 60 ml of dichloromethane and 40 ml of methanol, and the mixture is then stirred for 30 minutes. The reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by FC (700 g of silica gel, dichloromethane/diethyl ether=98:2), yielding the title compound: Rf (dichloromethane/diethyl ether=97:3)=0.50; HPLC Rt =14.32 minutes; FAB-MS (M+H)+ =262.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:36][C:37]1[N:42]=[CH:41][CH:40]=[N:39][CH:38]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH:40]=[N:39][CH:38]=[C:37]([Cl:36])[N:42]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: Clc1cnccn1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-c4cncc(Cl)n4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and 6-chloropyrazine. Light brown solid. MS (EI): 618.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4]>[Pd].CO>[F:1][C:2]([F:13])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4]
Reactant: COc1ccccc1C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1C(O)C(F)(F)F
Reaction time: 12 h
Yield: 99 %

Procedure:
10% palladium on carbon (1.5 g) was added to a solution of 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone (3.0 g) in methanol (50 ml). The resultant was hydrogenated at room temperature for 12 hrs. After which time the catalyst was filtered off through a plug of celite and the solvent concentrated in vacuuo. The crude was purified by column chromatography on silica gel eluting with 100% hexanes the 80:20 hexanes:ethylacetate to afford the title compound as a yellow oil (3.0 g). 1H NMR (CDCl3): δ 3.75 (d, J=2.56 Hz, 1H), 3.96 (s, 3H), 5.35 (m, 1H), 7.05 (m, 2H), 7.50 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2csc(N3CCOCC3)n2)c(OC)c1)OCC
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.25 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.36 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([O-:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O-:23])=[O:22])[CH2:16][C:17]([O-:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([O-:7])=[O:6].[Na]>>[CH2:13]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:1][CH2:2][N:3]([CH2:4][C:5]([OH:7])=[O:6])[CH2:8][C:9]([OH:11])=[O:10])[CH2:14][N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Agent: [Na]
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O

Procedure:
diethylenetriaminepentaacetate, sodium salt.
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])CS.C(N(CC)CC)C>C(O)C>[CH2:16]([O:15][C:11]([C:1]1[S:2][C:3]([S:4][CH3:5])=[C:6]([C:9]#[N:10])[C:7]=1[NH2:8])=[O:14])[CH3:17]
Reactant: CCOC(=O)CS
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(SC)c(C#N)c1N
Temperature: 65 °C

Procedure:
Stir a slurry of bis(methylthio)methylenepropanedinitrile, prepared in preparation 34, (69.29 g, 407 mmol) in ethanol (1.1 L) under nitrogen at rt then add ethyl thioglycolate (44.9 mL, 407 mmol) followed by triethylamine (56.7 mL, 407 mmol). Heat the resulting mixture at 65° C. for 30 min. Cool slowly to 35° C. over 45 min, then cool to 3° C. over 20 min and maintain at that temperature for 20 min. Collect precipitate by filtration, wash with cold ethanol and ether to afford the title compound: 1H NMR (CDCl3) δ 5.77 (bs, 2H), 4.28 (q, J=7.1, 2H), 2.64 (s, 3H), 1.33 (t, J=7.1, 3H); TLC (25% hexanes/ethyl acetate) Rf=0.25).
Reaction SMILES: [C:1]([N:9]1[C:33](=[O:34])[CH:32]=[CH:31][N:11]([C@@H:12]2[O:30][C@H:27]([CH2:28][OH:29])[C@@H:25]([OH:26])[C@H:13]2[O:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[C:10]1=[O:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[CH:59]=[CH:58][C:41]([C:42](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1>N1C=CC=CC=1>[C:1]([N:9]1[C:33](=[O:34])[CH:32]=[CH:31][N:11]([C@@H:12]2[O:30][C@H:27]([CH2:28][O:29][C:42]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:41]3[CH:40]=[CH:39][C:38]([O:37][CH3:36])=[CH:59][CH:58]=3)[C@@H:25]([OH:26])[C@H:13]2[O:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[C:10]1=[O:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)n(C(=O)c2ccccc2)c1=O)OCC(F)(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)n(C(=O)c4ccccc4)c3=O)[C@H](OCCC(=O)OCC(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The N3-benzoyl-2′-O-[2-(2,2,2-trifluoroethoxy)carbonylethyl]uridine (750 mg, 1.5 mmol) synthesized in Example 14 was dissolved in dried pyridine (15 mL). To the solution was added 4,4′-dimethoxytrityl chloride (763 mg, 2.3 mmol), followed by stirring at room temperature for 1.5 hours. The reaction was terminated by adding water thereto. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography eluting with hexane-chloroform (1:1, v/v) to give the title compound as a white foam-like material (750 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].C(N(CC)CC)C.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[I-].[K+]>O1CCCC1.ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=2)[CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 98 %

Procedure:
Ethyl-4-bromobutyrate (390 mg, 2.00 mmol) and triethylamine (280 μL; 2.00 mmol) were added to a solution of 1-(4-trifluoromethylphenyl)-piperazine (460 mg; 2.00 mmol) in tetrahydrofuran (3 mL). Potassium iodide (332 mg; 2.00 mmol) was added and the resulting suspension is irradiated in a mono-mode microwave oven for 2 hours at 100° C. The suspension is then diluted with dichloromethane (15 mL) and washed twice with water (5 mL). The organic phase is then dried over sodium sulphate and is concentrated under reduced pressure to afford the desired product (660 mg; 1.96 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:17]=[CH:18][N:19]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=2.[Br:20]N1C(=O)CCC1=O>ClCCl>[Br:20][C:17]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:19][CH:18]=1)=[CH:9][C:8]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:7][CH:6]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1nccn12
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1ncc(Br)n12
Temperature: 30 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 4-chloro-7-(trifluoromethoxy)imidazo[1,2-a]quinoxaline (5.4 g, 18.8 mmol, 1 eq) prepared as described in example 7 step 4 in dichloromethane (94 mL) is added N-bromosuccinimide (5.0 g; 28.2 mmol; 1.5 eq). The solution becomes green during the addition. The solution is allowed to stir for 7 hours at 30° C. until completion of the reaction. Then, the solution is concentrated under vacuum and purified by chromatography on a silica gel column (chloroform/cyclohexane 7:3) to afford the title compound still contaminated by 10% of residual N-bromosuccinimide (7.2 g; 17.7 mmol; 94%). The compound is used as such in the next step without further purification.
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:9][CH:8]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>O>[N:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:11]1[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN(c2ccccn2)c2ccccn2)nc1
Reaction time: 0.75 h
Yield: 55.7 %

Procedure:
To a flask were added 5.2 g pulverized potassium hydroxide and 35 ml dimethylsulfoxide. After adding 3.4 g 2,2′-dipyridylamine, the mixture was stirred under nitrogen for 45 minutes, when 3.3 g 2-(chloromethyl)pyridine hydrochloride was added. After stirring for 1 hour, 100 ml of water was added and the product was extracted with 60 ml of 50% ethyl acetate, 50% hexane. The organic layer was washed with 30 ml water and the solvent was removed. The residue was added to 5 ml hot ethanol, and 20 ml of water was added. After cooling to 5 C, the solid was filtered and washed with water. The product was dissolved in 20 ml hot ethanol and treated with 150 mg activated carbon. After hot filtration through celite, 40 ml of water were added and the mixture was cooled to 5 C. The product was filtered, washed with 20 ml 20% ethanol in water, and dried resulting in 2.9 g of an off-white solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:29]([NH:31][CH2:32][CH2:33][OH:34])[CH3:30]>>[CH2:29]([N:31]([CH2:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:32][CH2:33][OH:34])[CH3:30]
Reactant: CCNCCO
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CCN(CCO)CCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and 2-Ethylaminoethanol were converted to yield 2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanol as light yellow oil, MS: 423 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:48])([CH3:47])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]([C:31]#[N:32])[N:30]=3)=[O:25])=[C:19]([C:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl.CCO>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH2:7][C:8]([CH3:48])([CH3:47])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[NH:30][C:29]([C:31]#[N:32])=[CH:28][N:27]=3)=[O:25])=[C:19]([C:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)N1CCC(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of {2-[4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (40 mg, 0.050 mmol) in 2 mL of DCM and 20 μL of EtOH was added 1.5 mL of TFA. The solution was stirred for 3 h at 25° C., diluted with 2 mL of EtOH and concentrated in vacuo. Trituration of the residue with ether afforded 8.4 mg (29%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.10 (d, 1H, J=8.4 Hz), 8.00 (s, 1H), 7.16 (d, 1H, J=8.4 Hz), 7.07 (s, 1H), 5.79 (s, 1H), 4.55-4.48 (m, 1H), 3.30 (s, 6H), 2.89-2.87 (m, 2H), 2.40-2.25 (m, 4H), 1.96-1.93 (m, 2H), 1.86-1.83 (m, 6H), 1.64-1.61 (m, 2H). Mass Spectrum (ESI, m/z): Calcd. for C26H33N6O2, 461.2 (M+H). found 461.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[N:15]O)[CH:6]=[CH:7][CH:8]=1.[OH2:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[NH:15][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCC2=NO)c1
Reactant: O
Product: COc1cccc(C2CCCCC(=O)N2)c1
Temperature: 117.5 °C
Reaction time: 0.33 h

Procedure:
2-(3-Methoxyphenyl)-cyclohexanone oxime, as described above in Step B, (0.62 g, 2.8 mmol) and polyphosphoric acid (20 g) were combined and heated at 115-120° C. with stirring for 20 min. The dark mixture was poured into ice (100 g) with stirring, diluted with H2O (200 mL), then extracted with CHCl3 (5×100 mL), the organic layers combined, washed with brine, dried (MgSO4), filtered, and concentrated to dryness to give the title compound after SiO2 chromatography (CHCl3:MeOH, 100:1 to 20:1).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:4][C:5](OC)=[O:6])#[N:2]>[Ni]>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][CH:3]1[CH2:1][NH:2][C:5](=[O:6])[CH2:4]1
Reactant: COC(=O)CC(C#N)Cc1ccc(Cl)cc1Cl
Agent: [Ni]
Product: O=C1CC(Cc2ccc(Cl)cc2Cl)CN1

Procedure:
In the same manner as Example 1-(d), 5 g of methyl 3-cyano-4-(2,4-dichlorophenyl)butyrate was reduced with the aid of Raney's nickel to obtain the contemplated product 4-(2,4-dichlorobenzyl)-2-pyrrolidinone.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH:45]6[CH2:47][CH2:46]6)[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH:45]6[CH2:46][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C4CC4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C4CC4)cc2)CCN3CC(C)C)cc1
Yield: 73.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylimidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (700 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (389 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylimidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (526 mg) (Compound 367) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][N:6]=1)=[O:4].[Br:17]Br.C(Cl)Cl.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Br:17])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCCCC2)cn1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCCC2)c(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
A mixture of 0.625 g (2.8 mmol) 5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester, 1.12 g (7 mmol) Br2 and 0.142 g (0.48 mmol) FeBr3 in 10 mL CHCl3 was stirred at room temperature for 16 h. The mixture was treated with DCM and water and the organic layer separated and dried with MgSO4. 0.12 g (14%) of the title compound was obtained after evaporation as light yellow crystals which were used without further purification. m/z (ES+): 299.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Br[C:17]1[CH:30]=[CH:29][C:20]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1>>[N:23]1([C:21]([C:20]2[CH:19]=[CH:18][C:17]([NH:1][C:2]3[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:3]=3)=[CH:30][CH:29]=2)=[O:22])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NC(=O)c1cn(-c2ccccc2)nc1N
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Product: NC(=O)c1cn(-c2ccccc2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
3-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carboxamide was prepared according to the general procedure in Example 1 Step 4 using 3-amino-1-phenyl-1H-pyrazole-4-carboxamide (52 mg, 0.257 mmol) and 4-(4-bromobenzoyl)morpholine (69.5 mg, 0.257 mmol) as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[Na+]>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)CCCc1c(C)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c2ccccc2c1CCCC(=O)O
Temperature: 20 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of methyl 4-(2-methylindol-3-yl)-butyrate (1.65 g) in methanol (50 ml) was added 1N aqueous sodium hydroxide (18 ml) at 20° C. and the mixture was stirred at 20° C. for 3 hours. After evaporation of the solvent, the residue was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was washed with hexane to give 4(2-methylindol-3-yl)butyric acid (1.23 g) as reddish brown crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].[Cl-].[NH4+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(C)CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)CCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
515 mg (1.32 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1l-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 160 mg of sodium hydride (60% oil dispersion) and 0.38 ml of 1-bromo-4-methylpentane were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=6:1) to give 334 mg (53%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(4-methylpentylamino)-4H-1-benzopyran-4-one.