Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])([CH2:11][N+:12]([O-])=O)[CH2:7]2)[CH2:2][CH3:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][CH2:11][C@@:8]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:7][C@H:6]2[C@@H:9]1[CH:10]=[C:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2
Reactant: CCCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCCC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 40.4 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-propyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g, 4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6 mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (425.1 mg, 43%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:31]1[C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:14][O:13][C:12]5[CH:15]=[C:16]6[C:20](=[CH:21][C:11]4=5)[CH2:19][CH2:18][O:17]6)[C:2]3=[O:1])=[CH:30][CH:29]=2)=[N:28][N:33]=[N:32]1
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1N(Cc2ccc(-c3nnn[nH]3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A round bottom flask was charged with 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (0.50 g, 1.27 mmol), sodium azide (0.21 g, 3.17 mmol), and triethylamine hydrochloride (0.45 g, 3.17 mmol) in toluene (20 mL). The reaction mixture was refluxed under argon for 24 h. After cooling to ambient temperature, the product was extracted with water. 36% hydrochloric acid was added dropwise to the aqueous layer. The solid was filtrated and dried under reduced pressure to afford 1′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.38 g, 58%); 1H NMR (300 MHz, CDCl3) δ8.02 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.47 (s, 1H), 6.40 (s, 1H), 5.01 (ABq, 2H), 4.79 (ABq, 2H), 4.53-4.38 (m, 2H), 3.03-2.82 (m, 2H); 13C NMR (75 MHz, CD3OD) δ177.6, 161.6, 161.2, 142.5, 140.1, 132.6, 129.1, 128.6, 127.9, 124.2, 123.6, 120.8, 120.4, 119.4, 109.8, 92.9, 80.3, 72.5, 57.4, 43.3, 28.8; MS (ES+) m/z 437.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([Cl:15])[C:3]=1[C:4]#[N:5].C(OC([NH:23][C@@H:24]([CH3:27])[CH2:25]O)=O)(C)(C)C>>[NH2:23][C@@H:24]([CH3:27])[CH2:25][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([Cl:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1c(Cl)cc(-c2ccn[nH]2)cc1Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Product: C[C@H](N)Cn1ccc(-c2cc(Cl)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared from 2,6-dichloro-4-(1H-pyrazol-5-yl)benzonitrile (0.75 g, 3.15 mmol) and (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (0.552 g, 3.15 mmol) using the method of Example 34(c). Yield 0.121 g. 1H NMR (400 MHz; CDCl3): δ 1.15 (d, 3H), 1.54 (bs, 2H), 3.49 (m, 1H), 3.93 (dd, 1H), 4.14 (dd, 1H), 6.60 (d, 1H), 7.50 (d, 1H), 7.84 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3[C:15](=[O:18])[NH:16][CH2:17][C:13]=3[CH:12]=[C:11]([NH:19][C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[NH:26]C(=O)OC(C)(C)C)[N:10]=2)=[CH:4][C:3]=1[CH3:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:34])[CH:4]=2)[C:14]2[C:15](=[O:18])[NH:16][CH2:17][C:13]=2[CH:12]=1
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)ccc1F
Yield: 2.6 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(4-fluoro-3-methylphenylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50.0 mg, 0.106 mmol) and TFA (1 mL, 12.98 mmol) in DCM (0.5 mL) was stirred at RT for 1 hr. The resulting mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid (1 mg, 2.54%). 1H NMR (500 MHz, CD3OD) δ ppm 1.14-1.95 (m, 8 H), 2.28 (s, 3 H), 3.73 (br s, 1 H), 4.30 (s, 2H), 4.38 (s, 1 H), 6.17 (s, 1 H), 7.00 (t, J=9.03 Hz, 1 H), 7.41-7.54 (m, 2 H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][OH:44])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][O:44][S:46]([CH3:45])(=[O:48])=[O:47])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 120 h
Yield: 88.5 %

Procedure:
Triethylamine (0.200 ml, 1.434 mmol, 1.5 equiv) was added to a stirring solution of methyl (1S,4R)-4-hydroxy-4-{5-[3-(hydroxymethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate (513 mg, 0.956 mmol) in anhydrous dichloromethane (15 mL). The orange solution was cooled to 0° C. (water/ice) then charged with methanesulfonyl chloride (0.089 ml, 1.147 mmol, 1.2 equiv). The reaction mixture was allowed to slowly warm to 23° C. and stir for 5 d. The mixture was partitioned between methylene chloride (2×90 ml) and water (95 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-{[(methylsulfonyl)oxy]methyl}-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (520 mg, 71%), as an orange-yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.79 (bs, 1H), 8.66 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.23 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 4.59 (s, 1H), 3.90 (s, 2H), 3.69 (s, 3H), 3.01 (s, 2H), 2.38-2.25 (m, 2H), 2.01 (m, 3H), 1.95-1.77 (m, 4H), 1.35-1.20 (m, 6H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17].CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][C:16]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:17]
Reactant: O=C(O)CCCBr
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)CCCBr
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-Boc-ethanolamine (2.10 g; 13.0 mmol), 4-Bromobutyric acid (2.18 g; 13.0 mmol) and N,N-dimethylaminopyridine (0.318 g; 2.60 mmol) were dissolved in CH2Cl2 (35 mL) and the mixture was cooled to 0° C.; EDAC (3.75 g; 13.6 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 18 hours. Then the mixture was diluted with CH2Cl2, washed with aqueous Na2HPO4 (5%, 2×50 ml) aqueous NaH2PO4, (5%, 2×50 ml) and brine (1×40 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:20]([C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Product: O=Cc1ccc(C(F)(F)F)cc1Oc1ccccc1
Yield: 78 %

Procedure:
Preparation analogous to Example 12 from 2-fluoro-4-trifluoromethyl-benzaldehyde and phenol. Yield: 78%, light-coloured crystals, crystallised from hexane; melting point: 57°-59° C.; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.71; 1H-NMR (CDCl3, 200 MHz): 7.08-7.50 (m, 7H): 8.05 (d, 1H) 10.60 (s, 1H). MS: 266/265 (M+), 217, 188.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH2:17]Cl)=[N:15][N:16]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:27][NH:28][CH3:29].[I-].[Na+]>>[CH3:27][N:28]([CH2:17][C:14]1[N:13]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:10][CH2:11][C:12]2=[N:16][N:15]=1)[CH3:29]
Reactant: CNC
Reactant: COc1cccc2c1C(c1cccc(SC)c1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [Na+]
Product: COc1cccc2c1C(c1cccc(SC)c1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 1, 7-methoxy-1-(chloromethyl)-6-[m-(methylthio)phenyl]-4H-s-triazolo-[4,3-a][1,4]benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[(dimethylamino)methyl]-7-methoxy-6-[m-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:33]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:34])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: C=CCN=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1
Yield: 60.5 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (100 mg, 0.28 mmol) in anhydrous DCM (3 mL) was added MP-carbonate (3.01 mmol/g; 275 mg, 0.84 mmol) and allyl isocyanate (25 μL, 0.28 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (18 mL), then evaporated to afford the desired product (72 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[C:20](O)=[O:21]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:14]=[CH:13][N:12]([C:20](=[O:21])[CH:19]([O:18][CH3:17])[C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[N:11]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2cc[nH]n2)cc(OC)c1Br
Reactant: COC(C(=O)O)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccn(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)n2)cc(OC)c1Br
Yield: 22 %

Procedure:
1-(3-(4-Bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was synthesized from 3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazole (prepared according to Journal of Org. Chem., 2003, 68, 5381) and 2-methoxy-2-(4-morpholinophenyl)acetic acid using the analogous procedure as for Example 51 to give 1-(3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl) ethanone as a solid (0.065 g, 22% yield). MS: m/z 516.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.B(O)(O)[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[N:32][NH:33]2.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]4[N:10]=[C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]5)[S:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cccc2[nH]ncc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
5-Chloro-2-((4-methylsulfonylpiperazin-1-yl)methyl)-7-morpholinothiazolo[5,4-d]pyrimidine, 1H-indazol-4-yl-4-boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were combined in a solution of equal parts sodium carbonate aqueous solution (1M, 3 eq) and acetonitrile. The solution was microwaved at 130° C. for eighteen minutes. An additional 0.1 equivalents of trans-dichlorobis(triphenylphosphine)palladium(II) was added and the solution was microwaved at 130° C. for an additional twenty minutes. Acetonitrile was added and the solution was filtered. The organic layer was purified by reverse phase chromatography to give the off white solid of 129.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:18][CH3:19])[CH2:5][CH:6]=[CH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH3:3]>C(O)(=O)C.O.[Fe]>[CH2:18]([N:4]([CH2:2][CH3:3])[CH2:5][CH:6]=[CH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH3:19]
Reactant: CCN(CC)CC=CCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)CC=CCc1ccc(N)cc1
Reaction time: 2 h

Procedure:
To a solution of 25 g (0.45 mole) of iron filings in 200 ml acetic acid, add a solution of 8.5 g (0.03 mole) N,N-diethyl-4-(4-nitrophenyl)-2-buten-1-amine hydrochloride in 50 ml water. Temperature rises to about 40° C., stir for 2 hr then filter off the excess iron. Adjust the pH of the filtrate to about 12 with sodium hydroxide, and extract with 3×100 ml methylene chloride. Take the combined extracts, dry over Na2SO4, then treat with charcoal. Evaporate the solvent to provide the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH3:3].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:29][CH3:30]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN(C)S(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(C)S(=O)(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (171.8 mg) obtained in Example 112-2 was dissolved in anhydrous methanol (7.0 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (65.0 mg) and sodium cyanoborohydride (49.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. The extract was dried with magnesium sulfate, and the solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (184.8 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH:10]#[C:11][CH:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CC(OC)(C)C>[C:11]([CH:12]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])#[CH:10]
Reactant: C#CC(O)CCCCC
Reactant: Oc1cccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C#CC(CCCCC)Oc1cccc(F)c1F
Reaction time: 19 h

Procedure:
2.4 g (0.33 mol) of 2,3-difluorophenol are initially introduced in 1.2 l of THF together with 50.0 ml (0.34 mol) of 1-octyn-3-ol and 94.1 g (0.36 mol) of triphenylphosphine, and a solution of 76.1 ml (0.39 mol) of DIAD in 100 ml of THF is added dropwise. After 19 h at RT, the batch is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane), giving 1-(1-ethynylhexyloxy)-2,3-difluorobenzene as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[OH:29][NH2:30].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[N:30]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1[C@H](CC(=O)c1ccnc(CO)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1[C@H](C/C(=N\O)c1ccnc(CO)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-(hydroxymethyl)pyridin-4-yl)propan-1-one (example 282, step 1) and hydroxyl-amine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=459.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.S(=O)(=O)([OH:17])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([C:13]([OH:17])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2cc(C)oc12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)c2cc(C)oc12
Temperature: 0 °C

Procedure:
To a well stirred solution of 7-methoxy-2-methylbenzo[b]furan-4-carboxaldehyde (from step 3) (4.0 g, 21.05 mmol) in acetone (40.0 mL) was added a solution of sulphamic acid (2.4 g, 25.26 mmol) in water (10.0 mL) followed by addition of a solution of sodium chlorite (2.8 g, 31.57 mmol) at 5-10° C. Ice cold water (250 mL) was added to reaction mixture and the product separated was filtered and dried at 60-70° C. to give intermediate-4 (3.2 g) as white solid.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([O:26][CH3:27])[C:15]([CH3:25])=[C:16]([O:23][CH3:24])[C:17]=3[CH2:21][CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:31])(=O)=O>>[Cl:31][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([O:26][CH3:27])[C:15]([CH3:25])=[C:16]([O:23][CH3:24])[C:17]=2[CH2:21][CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Product: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 22 %

Procedure:
By the method of Example 21 phenylthiomethylation of 4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.65 g) with chloromethyl phenyl sulfide (0.24 mL) gave 2-phenylthiomethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, reaction of which with sulfuryl chloride gave 2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, 0.16 g, 22% yield.
Reaction SMILES: C([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][NH:31][CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:6]=12)(=O)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[CH2:17][CH:16]([CH2:29][CH2:30][N:31]([CH3:32])[S:34]([CH3:33])(=[O:36])=[O:35])[N:7]3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]([OH:4])=[C:6]3[C:19]2=[O:20])=[CH:23][CH:24]=1
Reactant: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)S(C)(=O)=O)CN(Cc1ccc(F)cc1)C2=O

Procedure:
2-(4-Fluorobenzyl)-7-isopropyl-4-[2-(methylamino)ethyl]-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate (Example 67, Step 2, 37 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was treated with a large excess of reagents (70 μL MsCl, 270 μL triethylamine and 20 mg DMAP). Stirring the reaction at ambient temperature over night gave complete conversion to the sulfonamide with exchange of the 9-acetate to the 9-mesylate. The solvent was removed under a steady nitrogen stream at 50° C. and the residue dissolved in MeOH (1 mL) and treated with a solution of sodium methoxide in MeOH (25 wt %, 2.5 mL). After four days of stirring at ambient temperature, cleavage of the 9-mesylate to the 9-hydroxy was complete. The mixture was quenched by the addition of TFA and water and was then concentrated under a steady stream of nitrogen at 50° C. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 11.73 (s, 1 H), 7.38-7.27 (m, 2 H), 7.09-7.05 (m, 2 H), 5.22-5.15 (m, 1 H), 4.96 (d, J=14.5 Hz, 1 H), 4.78-4.76 (m, 1 H), 4.37 (d, J=14.0 Hz, 1 H), 3.72 (dd, J=1.5, 14.0 Hz, 1 H), 3.62 (dd, J=3.8, 14.0 Hz, 1 H), 2.83 (s, 3 H), 2.80-2.66 (m, 5 H), 1.90-1.83 (m, 1 H), 1.56-1.49 (m, 1 H), 1.47 (d, J=7.0 Hz, 6 H). HRMS (APCI) M+H: calcd for (C21H28FN4O6S)+ 483.1708. found 483.1729.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CSc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3SC)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 43.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylthiophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.077 g, 0.16 mmol) obtained in step 2 and ethanesulfonamide (0.084 g, 0.80 mmol), the title compound (0.040 g, 43%) was obtained.