Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCC(ON2C(=O)C(S([O-])(=O)=O)CC2=O)=O)=[O:11])[C@H:3]2[NH:32][C:33]([NH:35][C@@H:2]12)=[O:34].[Na+].C(=O)([O-])[O-:38].[Na+].[Na+]>>[OH:38][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:35][C:33]([NH:32]2)=[O:34])[CH2:1][S:5]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)[O-])C1=O
Agent: [Na+]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 8 h

Procedure:
The RA-NAH (10 mg) obtained in the above was dissolved in 0.5 ml of 0.1 M sodium carbonate aqueous solution, subsequently adding 3 mg of sulfo-NHS-LC-biotin (mfd, by Pierce Chemical Company) thereto followed by overnight incubation at 4° C. After overnight dialysis against distilled water thereafter, the dialyzed liquid was lyophilized to obtain the polysaccharide of the present invention in which biotin is bound to the reducing end of NAH (to be referred to as “NAH-biotin” hereinafter) (8 mg).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16]([C@H:18]1[O:20][CH2:19]1)Cl>CN(C)C=O>[O:20]1[CH2:19][C@H:18]1[CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: ClC[C@@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2C[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a stirred solution of carbazole (5.0 g, 29.9 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 85% aqueous potassium hydroxide (2.171 g, 32.9 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath and (S)-(+)-epichlorohydrin (4.68 mL, 59.8 mmol) was added. The mixture was stirred overnight at room temperature, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by silica gel column chromatography (30% methylene chloride/hexanes) to afford the desired product as a white solid (3.9 g, 58%). [α]D-10.4 (c 1.92, CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.60-7.40 (m, 4H), 7.35-7.20 (m, 2H), 4.64 (dd, 1H, J=15.9, 3.3 Hz), 4.41 (dd, 1H, J=15.9, 4.8 Hz), 3.37 (m, 1H), 2.82 (t, 1H, J=4.2 Hz), 2.59 (dd, 1H, J=4.5, 2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](N3CCN(CCCS(C)(=O)=O)CC3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:55]1([CH2:61][C:62]([N:64]2[CH2:68][CH2:67][CH2:66][CH2:65]2)=[O:63])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:58]3[CH2:57][CH2:56][N:55]([CH2:61][C:62](=[O:63])[N:64]4[CH2:65][CH2:66][CH2:67][CH2:68]4)[CH2:60][CH2:59]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:47])([CH3:48])[CH3:49])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35° C. at 100 bar, eluting with 15% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H50N6O5SCl3 [(M+H)+] 831.2624, observed 831.2625.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[C:28]1([S:34]([OH:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:37])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)c1ccccc1
Agent: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Solvent: CCO
Product: O=S(=O)([O-])c1ccccc1
Temperature: 0 °C

Procedure:
A reactor was charged with 0.123 g (S)-zopiclone. To the reactor was added 0.056 g benzenesulfonic acid. The reaction was agitated and charged with 17.2 g ethanol. The reaction was cooled to 0° C., and the reaction was allowed to stir for greater than one hour after a slurry appeared. The reaction mixture was filtered and washed once with 0.5 g ethanol, dried in vacuo at approximately 50° C. for approximately 6 h to yield the titled compound in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CC(=O)Nc1ccc(OCCn2c(C)cc3c(Cl)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1 H), 7.89 (d, J=1.1 Hz, 1 H), 7.77 (d, J=8.5 Hz, 1 H), 7.53 (d, J=8.5 Hz, 1 H), 7.39 (d, J=8.9 Hz, 2 H), 6.73 (d, J=8.9 Hz, 2 H), 4.62 (t, 2 H), 4.19 (t, 2 H), 2.48 (s, 3 H), 1.95 (s, 3H); MS (ES) m/z 368 (M+1).
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([OH:15])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>O1CCCC1.C(O)C>[CH3:16][N:18]([CH3:19])[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethylchloroformate (18.3 ml) was added slowly to a solution of heptanoic acid (20.0 g) and triethylamine (26.7 ml) in tetrahydrofuran (250 ml), maintained at -10°. The resulting mixture was stirred at 10° for 0.75 hour, cooled to 5° and a 33% solution of dimethylamine in ethanol (41.6 ml) added dropwise. This mixture was then allowed to warm to room temperature and stirred for 4 hours. The mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in chloroform (250 ml) and washed with 1% aqueous sodium carbonate solution (200 ml) and water, then dried and evaporated. The residual oil was chromatographed on silica gel to give N,N-dimethylheptanamide (14.1 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cc(C(=O)O)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c(Oc2ccc(Br)cc2)cc1F
Temperature: 110 °C
Yield: 94.8 %

Procedure:
A mixture of 2-bromo-4-fluoro-5-methoxybenzoic acid 1 (1.0 kg, 4.02 mol), 4-bromophenol (4.41 mol, 1.05 equiv, 729.5 g) and Cs2CO3 (12.06 mol, 3 equiv. 3.92 kg) in anhydrous DMF (12 L) was degassed with N2 for 30 min. To this mixture was added copper (I) triflate toluene complex (2:1) (0.04 equiv. 83.12 g) and the mixture was further degassed again with N2 for 15 min. The resulting mixture was heated at 110° C. for 4 days. The reaction mixture was cooled to ambient temperature and poured onto 5 L of ice water. The pH was adjusted to 1 with concentrated HCl and the aqueous layer was extracted with EtOAc (3×4 L). The combined extracts were washed with brine (2×2 L). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a thick brown oil. The brown oil was triturated with a 5% IPA/water mixture (5 L) at ambient temp to obtain a brown solid. The solid was filtered, washed with water and hexane and dried overnight under vacuum to afford 2-(4-bromophenoxy)-4-fluoro-5-methoxybenzoic acid (1.3 kg, 95% yield) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C@@H:9]([C@H:10]([O:26][C@@H:27]2[O:31][C@H:30]([CH2:32][NH2:33])[C@@H:29]([OH:34])[C@H:28]2[OH:35])[C@H:11]2[O:15][C@@H:14]([N:16]3[C:22](=[O:23])[NH:21][C:19](=[O:20])[CH:18]=[CH:17]3)[C@H:13]([OH:24])[C@@H:12]2[OH:25])[C:7](=[O:8])[N:6]([CH3:36])[C@H:5]([C:37]([OH:39])=[O:38])[C@@H:4](O)[CH2:3]1>Cl>[CH3:1][N:2]1[C@@H:9]([CH:10]([O:26][C@@H:27]2[O:31][C@H:30]([CH2:32][NH2:33])[C@@H:29]([OH:34])[C@H:28]2[OH:35])[C@H:11]2[O:15][C@@H:14]([N:16]3[C:22](=[O:23])[NH:21][C:19](=[O:20])[CH:18]=[CH:17]3)[C@H:13]([OH:24])[C@@H:12]2[OH:25])[C:7](=[O:8])[N:6]([CH3:36])[C:5]([C:37]([OH:39])=[O:38])=[CH:4][CH2:3]1
Reactant: CN1C[C@H](O)[C@@H](C(=O)O)N(C)C(=O)[C@@H]1[C@H](O[C@@H]1O[C@H](CN)[C@@H](O)[C@H]1O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: Cl
Product: CN1C(=O)[C@H](C(O[C@@H]2O[C@H](CN)[C@@H](O)[C@H]2O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)N(C)CC=C1C(=O)O
Yield: 20 %

Procedure:
An amount of caprazol was dissolved in an amount of iN aqueous hydrochloric acid and the resultant solution was heated at 100° C. for 3 hours, thereby to produce caprazene in the yield of 20%. About 20% of caprazol was left unreacted. Respective chemical structure of each compound was confirmed by NMR analysis. The resulting reaction solution was concentrated under a reduced pressure and the resulting residue was subjected to a silica-gel column chromatography. Thus, there can be separated caprazene and caprazol, from each other.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[CH:9]=[C:8]1[CH2:18]O)[CH3:6]>ClCCl>[C:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:8]([CH2:18][Br:2])[N:7]2[CH2:5][CH3:6])=[CH:11][CH:12]=1)#[N:17]
Reactant: CCn1c(CO)cc2ccc(C#N)cc21
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCn1c(CBr)cc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 500 ml flask, 18.2 g of 1-ethyl-2-(hydroxymethyl)indole-6-carbonitrile was dissolved in 200 ml of dichloromethane and then cooled to 0° C. 3.45 ml of PBr3 was slowly added thereto, and the mixture was stirred for 4 hours at room temperature. dichloromethane was then added and the reaction mixture was washed with aqueous Na2CO3 solution, diluted with water and then extracted three times with dichloromethane. The organic extracts were combined, dried over MgSO4 and then evaporated to obtain 6-cyano-1-ethyl-2-bromomethyl indole. The resulting product was dissolved in 200 ml of toluene and 30.9 g of triphenylphosphine was added thereto. The mixture was stirred for 10 hours at refluxing temperature and then cooled to room temperature. To this reaction solution was added diethyl ether, and the resulting precipitate was then filtered, washed several times with diethyl ether and dried to obtain 29 g of the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:64](Cl)(=[O:68])[CH:65]([CH3:67])[CH3:66]>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:64](=[O:68])[CH:65]([CH3:67])[CH3:66])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(C)C(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(=O)C(C)C)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with isobutyryl chloride according to General Procedure F to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-7-[2-(isobutyrylamino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester. This ester, upon hydrolysis according to General Procedure B, gave the title compound. LCMS (m/z): 980.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23]C)=[O:22])=[C:8]2[CH3:28])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([OH:23])=[O:22])=[C:8]2[CH3:28])=[CH:29][CH:30]=1
Reactant: COC(=O)c1cccc(-c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)c(-c1cccc(C(=O)O)c1)c(C)n2Cc1ccc(Br)cc1
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of the ester from Step 4 (445 mg, 0.96 mmol) and 2N NaOH (1.5 mL, 3 mmol) in ethanol (10 mL) was heated to reflux for 2 h then it was cooled and kept at 25° C. for 16 h. Ethanol was removed and the residue dissolved in water (20 mL). 1N HCl (5 mL) was added dropwise and under vigorous stirring; the solid was filtered and dried. A swish in Et2O/hexane mixture yielded the pure product (350 mg) Anal. calcd. for C24H20BrNO3 : C, 64.01; H, 4.48; N, 3.11. Found: C, 63.56; H, 4.35; N, 3.12.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.N([O-])=O.[Na+].[CH3:21][OH:22]>O>[CH3:21][O:22][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:3]2([NH2:2])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(CC2(N)CCCC2)cc1
Reactant: CO
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC2(N)CCCC2)cc1
Reaction time: 2 h

Procedure:
1.4 g (6.17 mmol) 4-(1-aminocyclopentylmethyl)-phenylamine hydrochloride are placed in 25 mL methanol and at 0° C. combined with 2.24 mL (27 mmol) conc. hydrochloric acid. At this temperature 0.51 g (7.41 mmol) sodium nitrite in 1 mL water are added dropwise within 30 minutes. After 2 hours stirring the reaction mixture is allowed to come up to ambient temperature and then refluxed for 3 hours. The solvents are distilled off and the residue is combined with ethyl acetate. It is washed with aqueous ammonia solution, dried with sodium sulphate and evaporated down. The residue is dissolved in ethanol and combined with 10% hydrochloric acid in ethanol. The product precipitated as a salt is filtered off, washed with ethanol and dried. Yield: 0.56 g (27% over 2 steps, hydrochloride), mass spectroscopy: [M+H]+=206.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:4]=2[S:5][C:6]=1C(O)=O.[NH:15]1[CH2:21][CH2:20][CH2:19]N[CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:3]2[C:2]([N:1]3[CH2:19][CH2:20][CH2:21][NH:15][CH2:16][CH2:17]3)=[CH:6][S:5][C:4]=2[CH:10]=1
Reactant: C1CNCCNC1
Reactant: Nc1c(C(=O)O)sc2cc(F)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc2c(N3CCCNCC3)csc2c1
Temperature: 25 °C

Procedure:
Heat a solution of 3-amino-6-fluoro-benzo[b]thiophene-2-carboxylic acid (5.0 g, 24 mmol) in 1-methyl-2-pyrrolidinone (5 ml) to 100° C. for 2 h., and then, introduce a stream of nitrogen, to cool the solution to room temperature. Add homopiperazine (9.5 g, 95 mmol) and p-toluene sulfonic acid monohydrate (9.0 g, 47 mmol) and heat the mixture to 145° C. for 4 h. After that time, cool the reaction mixture to room temperature, dilute with ethyl acetate (30 mL) and wash with brine (3×15 mL). Separate the organic layer and dry over MgSO4. Evaporate the solvent and purify the crude product by column chromatography (SiO2, 100 g CH2Cl2/MeOH 9:2, then
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:23][C:21]1[CH:20]=[C:4]([CH:3]=[C:2]([F:1])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cc(F)cc(F)c1
Yield: 85 %

Procedure:
Dimethyl 2-(3,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.459 g, 25.84 mmol) was dissolved in acetonitrile (85 mL) and water (1.7 mL). Lithium bromide (17.95 g, 206.74 mmol) and triethylamine (14.33 mL, 103.37 mmol) were added. The suspension was heated to reflux 1.5 h before water (100 mL) and MTBE (300 mL) were added. The organic phase was extracted with water (×2). The combined water phases were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (×2). The combined organic phases were washed with water, dried with MgSO4, filtered through celite and concentrated. The crude product was redissolved in MTBE and washed with 0.1 M HCl (×2) and water. The organic phase was dried with MgSO4 and concentrated to give 2-(3,5-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.88 g, 85%). MS m/z 314 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1.[BH4-].[Na+].S([O-])(O)(=O)=O.[K+]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1
Reactant: CC(=O)c1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Product: C=Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
The 2(2-hydroxy-5-acetylphenyl)2H-benzotriazole (2H5A) thus produced may then be (1) reduced with sodium borohydride followed by dehydration with potassium hydrogen sulfate to produce 2(2-hydroxy-5-vinylphenyl)2H-benzotriazole (2H5V), or (2) reacted with a methyl Grignard reagent and dehydrated with potassium hydrogen sulfate to produce 2(2-hydroxy-5-isopropenylphenyl)2H-benzotriazole (2H5P).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.BrBr>CCOCC>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([S:9][S:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:4][CH:5]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: BrBr
Solvent: CCOCC
Product: FC(F)(F)c1ccc(SSc2ccc(C(F)(F)F)cc2)cc1

Procedure:
To a solution of 4-(trifluoromethyl)benzenethiol (1 g) in Et2O was added bromine until orange color remained. The addition was stopped and the organic layer was washed with 1:1 aqueous saturated NaHCO3/10% aqueous Na2S203, dried over Na2SO4 and concentrated to give the title compound used as such.
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][C:10]([C-:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:22].ClC1C=C(C=CC=1)C(O)=[O:28]>C(Cl)(Cl)Cl>[CH:1]1([S:7]([CH2:8][CH2:9][C:10]([C-:12]2[CH:13]=[CH:14][CH:15]=[CH:16]2)=[O:11])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:22]
Reactant: O=C(CCSC1CCCCC1)[c-]1cccc1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: ClC(Cl)Cl
Product: O=C(CCS(=O)C1CCCCC1)[c-]1cccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(Cyclohexylthio)propionylferrocene (1.3g, 0.00366M) was dissolved in chloroform (30 ml) and the solution was cooled in ice/water. m-Chlorobenzoic acid (0.63g, 0.00366M) was then added slowly with stirring. Following the addition, stirring was continued at room temperature for 3 hours, and the resulting solution was washed with dilute sodium bicarbonate solution and water, before being dried over anhydrous sodium sulphate. Removal of the solvent on a rotary evaporator yielded a red oil which subsequently crystallised as orange needles of the title compound (1.15g) mp = 90°-1°.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[C:10]([N:26]2[C:35]3[C:30](=[C:31](F)[C:32]([F:38])=[C:33]([F:37])[C:34]=3[F:36])[C:29](=[O:40])[C:28]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:27]2)=[N:11][C:12]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:13]([F:15])[CH:14]=1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CCCCCC>[CH2:46]([NH:53][C:31]1[C:32]([F:38])=[C:33]([F:37])[C:34]([F:36])=[C:35]2[C:30]=1[C:29](=[O:40])[C:28]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:27][N:26]2[C:10]1[C:9]([F:8])=[CH:14][C:13]([F:15])=[C:12]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:11]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: NCc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
To 8 ml of toluene were added 1.58 g of ethyl 1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridine-2-yl]-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate together with 0.68 g of benzylamine, and the mixture was stirred at 110° C. for 20 minutes and allowed to cool. After adding 15 ml of toluene and 15 ml of n-hexane, the mixture was washed twice with 300 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 4 ml of ethanol, and the solution was allowed to stand, and the precipitate was collected by filtration and washed with ethanol to obtain 1.20 g of the title compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]([CH2:24][CH3:25])[CH2:22][OH:23]>>[OH:23][CH2:22][CH:21]([NH:20][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:24][CH3:25]
Reactant: CCC(N)CO
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: CCC(CO)Nc1cccc2nc(NC(=O)c3ccccc3)nn12

Procedure:
The title compound was prepared following procedure described for example 30, but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 52 mg; 0.19 mmol; 1.0 eq.) and 2-amino-1-butanol (0.2 mL) as a white powder (13 mg, 22%). HPLC, Rt: 2.25 min. (purity 90.7%). LC/MS, M+(ESI): 326.2.