Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[I-:11].[Na+].NCCN.N>[Cu]I.O.O1CCOCC1>[I:11][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: NCCN
Product: OCCc1ccc(I)cc1

Procedure:
0.474 g (2.48 mmol) of copper (I) iodide, 5 g (24.86 mmol 2-(4-bromophenyl)ethanol and 7.45 g (49.73 mmol) of sodium iodide are successively added to a flask under an argon atmosphere. Then 0.438 g (4.97 mmol) of dimethylenediamine and 25 mL dioxane are added and the reaction mixture is refluxed for 14 hours. Then the reaction mixture is combined with 20 mL concentrated ammonia solution at ambient temperature, with 100 mL of water diluted and extracted with dichloromethane. The organic phase is extracted three times with water and dried over sodium sulfate. Yield: 5.4 g (87.5% of theory); C8H9IO (M=248.06); calc.: molecular ion peak (M)+: 248; found: molecular ion peak (M)+: 248; Rf value: 0.6 (silica gel, dichloromethane/ethanol (10:1)).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:47])([CH3:46])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)[NH:9]1)=[O:7])(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:47])([CH3:46])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][C:50](=[O:51])[C:49]([F:54])([F:53])[F:48])[NH:9][CH:8]2[C:6]([OH:5])=[O:7])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CCOCCO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CCOCCOC(=O)C(F)(F)F)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl}-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 119b (0.49 g, 0.55 mmol) in dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-{2,2-dimethyl-4-[2-(2,2,2-trifluoro-acetoxy)-ethoxy]-butyl}-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow oil (0.37 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:11](=[S:13])[NH2:12])[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)[C:11]2[S:13][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(CCc2cccc(Br)c2)C(N)=S)cc1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(C(CCc2cccc(Br)c2)c2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 89.6 %

Procedure:
By a reaction in the same manner as in Example 178b and using the compound (3.15 g, 8.03 mmol) obtained in Example 181b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (3.22 g, 12.0 mmol), the title compound (4.03 g, 90%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[Br:19].C(S)CCC.[OH-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:17]([F:23])([F:22])[C:18]([Br:19])([F:21])[F:20]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1c(F)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCS
Product: Fc1cccc(Br)c1OC(F)(F)C(F)(F)Br
Temperature: 50 °C
Yield: 76.5 %

Procedure:
2-Bromo-6-fluorophenol (10.2 g, 53 mmol), potassium carbonate (7.3 g, 53 mmol), 1,2-dibromo-tetrafluoroethane (21 g, 80 mmol) and 1-butanethiol (1.1 g, 12 mmol) were combined in dry N,N-dimethylformamide (75 mL) and heated to 50° C. in a stirred pressure reactor. After cooling, the contents were mixed with 1.0 M sodium hydroxide (NaOH; 100 mL) and extracted three times with diethyl ether (80 mL portions). The combined extracts were washed with water (15 mL), 2.0 M NaOH (45 mL), dried (Na2SO4) and concentrated by rotary evaporation. The material was purified by silica gel chromatography eluting with hexane to afford the title compound as a clear liquid (15 g, 76%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.39 (m, 1H), 7.22-7.14 (m, 2H); EIMS m/z 368.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Si]([O:13][CH2:14][C:15]#[C:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])(C(C)(C)C)(C)C>CO>[F:19][C:18]([F:21])([F:20])[C:17]1[CH:16]=[C:15]([CH2:14][OH:13])[O:3][N:2]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cc(C(F)(F)F)no1
Yield: 31.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.694 g 0.010 mol, 1 equ) and 0.02 g sodium hydroxide in 25 mL methanol was added 5-(tert-butyldimethylsilyloxy)-1,1,1-trifluoropent-3-yn-2-one (2.66 g 0.010 mol, 1 equ) and the mixture was heated to reflux for 3 h. The reaction mixture was extracted with ethyl acetate and purified by chromatography on silica gel (50 g) using a gradient of heptane:ethyl acetate=9:1 to 1:1. to yield 0.524 g of the title compound as colorless oil, MS 167 (M.)+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:103]=[CH:102][C:66]([CH2:67][O:68][C:69]([NH:71][C@@H:72]([CH2:95][S:96][S:97][C:98]([CH3:101])([CH3:100])[CH3:99])[C:73]([NH:75][CH2:76][CH2:77][CH2:78][CH2:79][C@H:80]([NH:87][C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[C:81](OCC#N)=[O:82])=[O:74])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:64]=[CH:65][C:66]([CH2:67][O:68][C:69]([NH:71][C@@H:72]([CH2:95][S:96][S:97][C:98]([CH3:101])([CH3:100])[CH3:99])[C:73]([NH:75][CH2:76][CH2:77][CH2:78][CH2:79][C@@H:80]([NH:87][C:88]([O:90][C:91]([CH3:92])([CH3:93])[CH3:94])=[O:89])[C:81]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:82])=[O:74])=[O:70])=[CH:102][CH:103]=1)=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (30.3 mg, 0.048 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk24) (93 mg, 0.143 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (9 mL), and the mixture was stirred at room temperature for 4.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk25) (6.7 mg, 11%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([OH:35])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([O:35][CH3:37])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the product of Example 2 (1.0 mmol) dissolved in anhydrous DMF add solid K2CO3 (1.2 mmol, anhydrous) and CH3I (1.2 mmol). After stirring the reaction mixture at room temperature for 24 hours, concentrate the mixture in vacuo, dilute with CH2Cl2 and wash with water. Dry the organic phase over anhydrous MgSO4, filter and concentrate in vacuo to afford the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[C:29]([OH:33])(=[O:32])[CH2:30][SH:31]>>[C:29]([CH2:30][S:31][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)=[CH:16][C:3]1=2)([OH:33])=[O:32]
Reactant: O=C(O)CS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Product: O=C(O)CSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and thioglycolic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:16][C:17]1C=CC=C[C:18]=1N1CCN(CCO)CC1>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:18][CH2:17][OH:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Product: O=C(c1ccccc1)N1CCN(CCO)CC1
Yield: 90 %

Procedure:
2-(4-Benzoyl-piperazin-1-yl)-ethanol (38A) is prepared from 1-benzoyl-piperazine as described for 28A.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[CH:11]([N-]C(C)C)(C)C.[Li+].CI.O>C1COCC1>[CH3:11][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCOCC1
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Methyl tetrahydropyran-4-carboxylate (2.88 g, 20.0 mmol) was dissolved in THF (100 mL), and a 2.0 mol/L solution of lithium diisopropylamide in THF (22.0 ml, 44.0 mmol) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. Methyl iodide (4.98 ml, 40.0 mmol) was added dropwise to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford methyl 4-methyltetrahydropyran-4-carboxylate (1.93 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=O)[CH3:22]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:21]([CH3:22])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ncn2c1COC(=O)c1c(Cl)cccc1-2
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ncn3c2COC(=O)c2c(Cl)cccc2-3)no1
Yield: 66 %

Procedure:
7-Chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a]-[4,1]benzoxazepine-3-amidoxime (3 g, 0.01 mole) in acetic anhydride (9 ml) was heated at 150° C. for 3 hours. The crude product in ethyl acetate was chromatographed on silica and then crystallised from acetone to give the product (2.1 g, 66%), m.p. 253°-255° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:9][CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:9][CH2:10][OH:11])[CH:3]=1
Reactant: Oc1cccnc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccnc1

Procedure:
The yield of the title compound according to D1, starting from 3-hydroxypyridine, 2-chloroethanol and K2CO3 in DMF was 19%. The title compound has also been prepared according to EP 0 286 242 A2 starting from methyl [(3-pyridinyl)oxy]acetate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:14]1([N:13]([CH3:12])[C:2]2[C:3]3[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNC1CCCCC1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc2c(N(C)C3CCCCC3)ncnc2[nH]1
Yield: 57.7 %

Procedure:
The product from Method H (50 mg/0.298 mmol) was reacted with 100 mg (0.883 mmol) of N-methylcyclohexylamine as described in Method B. The reaction mixture was worked up as in Method B with the exception that ethyl acetate was used in place of ether. The title compound (42 mg, 58% yield) was obtained as a white solid. Mp 221° C. dec. 1H NMR (400 MHz, CDCl3) δ: 1.15-1.25 (m, 1H), 1.43-1.62 (m, 4H), 1.73 (br s, 1H, J=13.7 Hz), 1.82-1.90 (m, 4H), 2.41 (d, 3H, J=0.8 Hz), 3.21 (s, 3H) 4.63 (br s, 1H), 6.20 (s, 1H), 8.22 (s, 1H), 10.1 (br s, 1H). LRMS: 245 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].C(O)C>[CH3:21][C:9]1[CH:10]=[C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)NNc1cc(C)c(-c2ccc(Br)cc2)nn1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccccc2)nn1

Procedure:
A 4.0 g. portion of ethyl 3-[6-(p-bromophenyl)-5-methyl-3-pyridazinyl]carbazate and 0.9 g. of 10% palladium on carbon catalyst in 100 ml. of ethanol and 50 ml. of ammonium hydroxide is shaken under 40 lb. of hydrogen pressure for 4 hours with external heating of the bottle by means of a heated jacket. The reaction mixture is suction filtered and the filtrate is concentrated to a light yellow oil which is scratched with petroleum ether to give a white solid, m.p. 142°-145° C.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH:26]([C:28]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=1[O:35][CH3:36])O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH3:36])=[C:28]([CH:33]=1)[CH2:26][C:18]1[S:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1
Reactant: COc1ccc(Br)cc1C(O)c1cc2ccccc2s1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(Br)cc1Cc1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Then, Et3SiH (10.3 mL, 0.0642 mol) and BF3.Et2O (4.10 mL, 0.0321 mol) were added sequentially to a chloroform (110 mL) solution of (1-benzothien-2-yl)(5-bromo-2-methoxyphenyl)methanol (1.2 g, 0.0321 mol) at −15° C. After the mixture was stirred for 0.5 hours, a saturated sodium bicarbonate aqueous solution was added. The mixture was extracted with chloroform, and the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain a title compound (9.84 g, 92%) as a yellow crystal.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[Br:14]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.OS(O)(=O)=O>[Br:14][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of 4-trifluoromethoxybenzaldehyde (150 g, 0.79 mol) in a mixture of TFA (400 mL) and H2SO4 (80 mL) was added at 40–45° C. N-bromosuccinimide (281 g, 1.579 mol) in equal portion over 2 hours. The reaction mixture was stirred at 40–45° C. overnight, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water then treated with saturated NaHCO3 (800 mL) for 30 minutes. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered-and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (150.2 g, 60° C., 0.3 mm/Hg, 70%). 1H NMR (300 MHz; CDCl3): δ 7.49 (dd, J1=1.8 Hz and J2=8.7 Hz, 1H), 7.88 (dd, J1=2.1 Hz and j2=8.4 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:3][Cl:4].[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:16]([NH:20][C:21]([NH:15][S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][C:2]([Cl:1])=[CH:3][Cl:4])(=[O:13])=[O:14])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Temperature: 25 °C
Yield: 74.4 %

Procedure:
2-(1,2-Dichloroethen-1-yloxy)benzenesulfonamide (13.4 g), 12.4 g of n-butyl isocyanate and 15.2 g of anhydrous potassium carbonate were combined in 200 ml of dry tetrahydrofuran and heated to reflux for three hours. The mixture was then cooled to room temperature, filtered and the solvent removed by evaporation. The residue and precipitate were recombined and dissolved in 600 ml of water and the mixture acidified with 10% hydrochloric acid. The resultant precipitate was removed by filtration, washed with water, air dried and then washed with hexane. After drying in vacuo at 80° overnight, 13.65 g of solid product melting at 122°-125° was obtained.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1.[C:24]1([N:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([N:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:5][CH2:4]2)=[O:32])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(=O)N(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.5 g (18.0 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (K22.142) and 5.77 ml (41.4 mmol) TEA are placed in 70 ml abs. dichlormethane and cooled to ca. 0° C. under moisture exclusion. 4.58 g (19.8 mmol) N,N-diphenylcarbamic acid chloride are dissolved in 20 ml abs. dichlormethane and added dropwise. The mixture is stirred at RT overnight without further cooling. 4 ml (28.7 mmol) TEA are added and the red colored suspension is stirred a further 2 hours at RT. Subsequently, the batch is washed with 80 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2) and crystallized twice, each from 60 ml acetic acid ethyl ester, after drawing off the solvent. Beige colored crystals with a MP of 132–134° C.; yield: 5.3 g (60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:31][C:28]1[CH:27]=[CH:26][C:25]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]2)=[CH:30][CH:29]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Yield: 26 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.15 g, 0.54 mmol) and [4-(4-methyl-1,4-diazepan-1-yl)phenyl]amine (0.11 g, 0.54 mmol) were stirred in N,N-dimethylformamide (3 mL) with triethylamine (0.3 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol. The crude material is dissolved in a minimum of 5% methanol in chloroform and then passed through a Florisil plug, eluting with 5% methanol in chloroform. The filtrate is concentrated under reduced pressure to give and then dried under vacuum to give (4Z)-6-bromo-4-({[4-(4-methyl-1,4-diazepan-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (64 mg, 26%) as a rust colored powder.