Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([NH2:25])[CH:19]=1)=[O:4].[N:26]1[CH:31]=C[CH:29]=[CH:28][CH:27]=1.ClC(OC1C=CC=CC=1)=[O:34].C1(N)CC1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([NH:25][C:31]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:34])[CH:19]=1)=[O:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Reactant: CNC(=O)c1cc2c(Oc3ccc(Cl)c(N)c3)ccnc2cc1OC
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(Oc3ccc(Cl)c(NC(=O)NC4CC4)c3)ccnc2cc1OC
Reaction time: 1 h
Yield: 74.4 %

Procedure:
After dissolving N6-methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (179 mg, 0.50 mmol) in dimethylformamide (2 ml) under a nitrogen atmosphere, pyridine (0.061 ml, 0.75 mmol) and phenyl chloroformate (0.094 ml, 0.75 mmol) were added dropwise at room temperature and the mixture was stirred for 1 hour. Cyclopropylamine (0.2 ml) was added dropwise and the mixture was further stirred overnight. The reaction solution was distributed between ethyl acetate and water, washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the crystals precipitated from ethyl acetate were filtered out and blow-dried to obtain the title compound (163.9mg, 0.372 mmol, 74.3%) as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][S:13]([C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[N:21][CH:20]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of 4-fluoro-2-methyl-1-nitrobenzene (9.4 g), 6-(methylsulfonyl)pyridin-3-ol (10.0 g), potassium carbonate (8.8 g), and N,N-dimethylformamide (100 mL) was stirred at 60° C. for 24 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was added to a mixture of ethyl acetate-water. The precipitated solid was collected by filtration, washed with water and ethyl acetate and dried to give the title compound (8.28 g) as a pale-yellow solid. The filtrate was extracted with ethyl acetate, washed successively with aqueous citric acid solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (4.30 g) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.O[NH:16][C:17](=[NH:36])[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][N:22]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:16]=[C:17]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:36]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A mixture of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (245 mg, 1.143 mmol), ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylpropanoate (D103) (348 mg, 1.143 mmol), in DMF (5 ml) at room temperature was treated with N-ethyl-N-(1-methylethyl)-2-propanamine (0.240 ml, 1.372 mmol) followed by HATU (522 mg, 1.372 mmol). The resulting mixture was stirred at room temperature for 1 hour and at 80° C. overnight and then for a further 4 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed twice with H2O then brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (233 mg, 39%) as a cream solid. MS (ES) C25H27ClN4O4 requires 482, found 483 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[NH:12]C(=O)O[C:8](=[O:9])[C:7]=12.[NH3:15]>CN(C=O)C.O>[NH2:12][C:6]1[C:5]([CH3:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([NH2:15])=[O:9]
Reactant: N
Reactant: Cc1ccc(Cl)c2c(=O)oc(=O)[nH]c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C(N)=O)c1N

Procedure:
According to the procedure of example 3, in the reaction of 98.8 g (0.467 mol) of 6-chloro-3-methylisatoic anhydride in 330 ml of DMF with 42 ml (0.560 mol) of 25% strength aqueous ammonia solution in 140 ml of water and a further 110 ml of water, 24 g (37% of theory) of the title compound were obtained as a yellowish powder of m.p. 149-152° C.
Reaction SMILES: COC(OC)[CH2:4][N:5]([CH3:10])[C:6](=[O:9])[CH2:7][Cl:8].[CH3:13][CH:14]([OH:18])[CH:15]([OH:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][CH:15]1[CH:14]([CH3:13])[O:18][CH:4]([N:5]([CH3:10])[C:6](=[O:9])[CH2:7][Cl:8])[O:17]1
Reactant: COC(CN(C)C(=O)CCl)OC
Reactant: CC(O)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1OC(N(C)C(=O)CCl)OC1C
Temperature: 110 °C

Procedure:
N-(2,2-Dimethoxyethyl)-N-methyl-2-chloroacetamide (97.8 grams; 0.5 mole), 2,3-butanediol (45 grams) and 0.2 grams p-toluenesulfonic acid were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distilling head and condenser. The reaction mixture was heated at about 90° C. to 100° for period of 5 hours. Little reaction occurred as shown by the absence of methanol distilled. The reaction mixture was then heated at about 110° C., for about 2 hours at atmospheric pressure, then 1 hour at reduced pressure. Under these more rigorous conditions, methanol was formed and was distilled off. At the conclusion of the reaction, the reaction mixture was distilled and the fraction boiling at 127° C. to 130° C. at 0.55 mm Hg was the desired product N-(4,5-dimethyl-1,3-dioxolan-2-yl)-N-methyl-2-chloroacetamide. 1,3-dioxolan-2-yl)-N-methyl-2-chloroacetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:19]=[C:12]2[CH:13]=[CH:14][C:15]([CH2:17]O)=[CH:16][N:11]2[N:10]=1.P(Br)(Br)[Br:21]>C(Cl)Cl>[Br:21][CH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])[N:19]=2)[CH:16]=1
Reactant: BrP(Br)Br
Reactant: Cc1cccc(C)c1-c1nc2ccc(CO)cn2n1
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1nc2ccc(CBr)cn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of (2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (148 g, 0.584 mol) in DCM (2.96 L) is added PBr3 (237.3 g, 0.877 mol) at −40° C. The reaction mixture is allowed to warm to temperature and then stirred for a further for 2 hours at room temperature. The reaction is cooled to 0° C., quenched with ice cold water (1.5 L) and saturated sodium bicarbonate solution is added to adjust the pH ˜7.5 to 8. The mixture is diluted with DCM (2 L), the aqueous layer is separated and extracted with DCM (3 L). The organic extracts are combined, washed with water (2×3 L) and brine solution (3 L), dried the organic extracts over sodium sulphate, filtered and evaporated to dryness to give the title compound (140 g, 76%). LCMS m/z 316/318 79Br/81Br (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][C:59]=2[CH2:61]O)[CH2:54][CH2:53][C:52]21[O:66][CH2:65][CH2:64][O:63]2.C1COCC1>C(Cl)Cl.CCOC(C)=O>[CH2:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][C:59]=2[CH2:61][N:14]2[C:13]3[CH:18]=[C:19]([F:20])[C:10]([S:7]([N:6]([CH2:5][C:4]4[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=4[O:2][CH3:1])[C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:8])=[O:9])=[CH:11][C:12]=3[O:16][C:15]2=[O:17])[CH2:54][CH2:53][C:52]21[O:63][CH2:64][CH2:65][O:66]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Reactant: OCc1cccc2c1CC1(CC2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CC4(CC5)OCCO4)c3cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing N-(2,4-Dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydro-1,3-benzoxazole-6-sulfonamide (11-3) (2.13 g, 4.57 mmol), resin bound (PS) TRIPHENYLPHOSPHINE (5.27 g, 9.70 mmol) & DTBAD (2.187 g, 9.50 mmol) & (3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-8′-yl)methanol (19-3) (1.162 g, 5.28 mmol) was added anhydrous THF (40 ml). The reaction mixture was then capped (not under N2) & stirred at room temperature for ˜16 hours (overnight). Followed by LC/MS. The reaction mixture was diluted with DCM/EtOAc, filtered (to remove the resin), it was noticed that the filtrate was cloudy white so it was filtered to yield 3-((3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-8′-yl)methyl)-N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-4).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][CH2:32][CH:33]2[NH2:38]>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:38][CH:33]2[C:34]4[C:30](=[C:29]([O:28][CH3:27])[CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32]2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: COc1cccc2c1CCC2N
Product: COc1cccc2c1CCC2Nc1ccc2c(NS(=O)(=O)c3cc(F)cc(F)c3)cccc2n1

Procedure:
The title compound, MS: m/e=482.5 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonyl chloride and rac-4-methoxy-indane-1-ylamine
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH:23]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:23]([NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH2:22][C:21]([CH3:26])([CH3:25])[CH3:20])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)CC(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
Benzotriazole, 4-chlorobenzamide, 3,3-dimethylbutanal, and p-toluenesulfonic acid were processed as in Example 53A to provide the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]([CH3:12])=[C:7]([CH3:11])[C:8]=1[C:9]#[N:10])[CH3:2].[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:9]([C:8]1[C:7]([CH3:11])=[C:6]([CH3:12])[S:5][C:4]=1[N:3]([CH2:1][CH3:2])[C:22]([NH:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])#[N:10]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCNc1sc(C)c(C)c1C#N
Product: CCN(C(=O)NC(=O)c1ccccc1)c1sc(C)c(C)c1C#N

Procedure:
Prepared in a similar manner to Example 1a from 2-(ethylamino)-4,5-dimethylthiophene-3-carbonitrile (Example 21b) and benzoyl isocyanate. MS 328 (MH+).
Reaction SMILES: ClC1N=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.C[O:17]C1CCCN(CCN)C1.CCN(CC)CC.C[O:35][CH2:36][CH2:37]OC>>[N+:4]([C:5]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:6]=1[NH:7][C:36](=[O:35])[CH3:37])([O-:15])=[O:17]
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COC1CCCN(CCN)C1
Reactant: COCCOC
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C

Procedure:
A solution of the chloride 21 (2.0 g, 9.0 mmol), 2-(3-methoxy-1-piperidinyl)ethylamine (283) (1.8 g, 11.4 mmol) and Et3N (1.5 mL, 9.9 mmol) in DME (140 mL) was stirred at reflux temperature for 22 h. The solution was cooled to 20° C., the solvent evaporated and the residue purified by chromatography, eluting with 5% MeOH/DCM to give (i) starting material 21 (0.6 g, 30%) and (ii) 1-oxide 40 (1.9 g, 61%) as a yellow solid: mp 123-124° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.81 (br s, 1H, NH), 3.54-3.58 (m, 2H, CH2N), 3.35 (s, 3H, OCH3), 3.24-3.31 (m, 1H, CHO), 2.97-3.03 (m, 5H, H-6, H-8, CH2), 2.68-2.74 (m, 1H, CH2), 2.63 (dt, J=6.1, 2.4 Hz, 2H, CH2N), 2.14 (p, J=7.4 Hz, 2H, H-7), 1.96-2.07 (m, 3H, CH2), 1.71-1.78 (m, 1H, CH2), 1.45-1.58 (m, 1H, CH2), 1.17-1.27 (m, 1H, CH2); 13C NMR δ 158.6, 154.5, 148.7, 143.2, 129.8, 120.5, 114.6, 76.2, 57.8, 56.5, 56.1, 53.2, 38.0, 33.1, 32.3, 29.9, 25.7, 23.2; HRMS (FAB+) calcd for C18H26N5O2 (MH+) m/z 344.2087, found 344.2090.
Reaction SMILES: [NH2:1][C@H:2]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:34]([C:94]([O:96][CH2:97][CH:98]1[C:110]2[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=2)[C:104]2[C:99]1=[CH:100][CH:101]=[CH:102][CH:103]=2)=[O:95])[C@H:35]([C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:91](O)=[O:92])[CH2:68][C:69](=[O:90])[NH:70][C:71]([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)=[O:65])[CH3:63])=[O:60])[C@@H:52]([CH3:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>[NH:34]([C:94]([O:96][CH2:97][CH:98]1[C:110]2[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=2)[C:104]2[C:99]1=[CH:100][CH:101]=[CH:102][CH:103]=2)=[O:95])[C@H:35]([C:48]([NH:50][C@H:51]([C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:91]([NH:1][C@H:2]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:92])[CH2:68][C:69](=[O:90])[NH:70][C:71]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)[C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)=[O:65])[CH3:63])=[O:60])[C@@H:52]([CH3:58])[O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42]
Reactant: C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(C)(C)C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(C)(C)C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
0.4 g of H-Cys(Trt)-Pro-Wang resin are condensed in a peptide synthesizer (continuous flow principle) with Fmoc-Lys(Boc)-Thr(But)-Ala-Asn(Trt)-OH (SEQ ID NO:87), using a three-fold excess of the Fmoc peptide. The coupling is carried out at room temperature in DCCI/HOBt, to give Fmoc-Lys(Boc)-Thr(But)-Ala-Asn(Trt)-Cys(Trt)-Pro-Wang (SEQ ID NO:223) resin. Subsequent treatment with TFA/CH2Cl2 followed by removal of the Fmoc group with piperidine/DMF (20%) gives H-Lys-Thr-Ala-Asn-Cys(Trt)-Pro-OH (SEQ ID NO:92).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].[CH2:12]([Li])[CH2:13]CC.[Cl-].[CH3:18][SiH:19]([CH3:33])[CH:20]1[C:32]2[CH:31]=CC=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2.[Cl-].[NH4+]>CCCCCC.CCOCC>[CH3:33][Si:19]([CH3:18])([CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]([CH3:28])=[C:32]1[CH3:31])[CH:4]1[C:3]2[CH:11]=[CH:13][CH:12]=[CH:1][C:2]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: C[SiH](C)C1c2ccccc2-c2ccccc21
Reactant: [Li]CCCC
Reactant: CC1=Cc2ccccc2C1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2c3ccccc3-c3ccccc32)c2ccccc21
Yield: 26.2 %

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, the 1,2-dimethylindene (1.60 g, 11.09 mmol) synthesized above and dehydrated ether (40 ml) were introduced. To the flask, a hexane solution of n-butyllithium (11.6 mmol) was dropwise added at 0° C. with stirring. The temperature of the system was allowed to spontaneously and slowly rise to room temperature. After stirring over night, the reaction liquid became a milk white slurry. To the slurry, the dimethyl(9-fluorenyl)silane chloride (2.72 g, 10.51 mmol) synthesized above was added, followed by stirring at room temperature for 2 hours. The reaction liquid became a yellow slurry. To the slurry, N-methyl-2-pyrrolidine (0.1 g) was added, followed by stirring at room temperature for 1.5 hours. To the resultant mixture, 100 ml of ether and 100 ml of a saturated aqueous solution of ammonium chloride were added and the mixture was introduced into a separatory funnel to separate an organic phase. The organic phase was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was purified by column chromatography :developer: hexane) to obtain 1.01 g of a yellow powder (yield: 27%).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].C(OCCC)CC>C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:2]([O-:5])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Solvent: CCCOCCC
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Methanesulfonic acid (1.3 ml, dissolved in 11 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in absolute ethanol (38 ml) with stirring at room temperature, and 50 ml of dipropyl ether is added. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 180.3° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:40][CH2:41][CH2:42][CH3:43])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([C:20](=[O:37])[CH2:21][CH2:22][C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[O:24])[CH:19]=1)(=[O:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(OCC)(=O)C>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:40][CH2:41][CH2:42][CH3:43])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([CH:20]([OH:37])[CH2:21][CH2:22][C:23](=[O:24])[C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)[CH:19]=1)(=[O:13])=[O:12])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCOc1c(OC)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOc1c(OC)cc(C(O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(5-(2-t-butyldimethylsilyloxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (1.076 g, 1.70 mmole) at 0° C. in dry THF (40 mL) under nitrogen was treated with lithium tri-t-butoxyaluminum hydride (500 mg, 2 mmole), and the mixture was stirred at 0° C. for 1 hour. The reaction was allowed to warm to room temperature and stirred for 3 hours. The mixture was poured into ethyl acetate (500 mL), and the ethyl acetate solution was washed with 1 N HCl (2×100 mL), water and brine, dried over anhydrous MgSO4, and evaporated to dryness. The crude product was purified by flash column chromatography on SiO2 and eluted with 40% hexane ethyl acetate (3:2 v/v) to provide the pure title product as a thick syrup.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:26])[C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][N:23]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C(F)(F)F)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=2[S:8][CH:9]=1
Reactant: BrBr
Reactant: Cc1cccc2ccsc12
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c(Br)csc12
Yield: 10 %

Procedure:
25 g of 7-methylbenzo[b]thiophene are dissolved in chloroform and 27 g of bromine added at room temperature with stirring. After one hour the mixture is poured onto water and the organic phase separated, washed, dried and concentrated under vacuum. The title compound (contaminated with ca. 10% of 4-bromo-7-methylbenzo[b]thiophene) is obtained as an oil following vacuum distillation at 92°-98°/2.6 mbar.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=S)[S:10]C)[CH2:4][O:3]1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][C:9](=[S:10])[NH:15][NH2:16])[CH2:4][O:3]1
Reactant: NN
Reactant: CSC(=S)NCC1COC(C)(C)O1
Solvent: CCO
Solvent: O
Product: CC1(C)OCC(CNC(=S)NN)O1
Yield: 69.4 %

Procedure:
A mixture of methyl N-(2,2-dimethyl-dioxolan-4-yl-methyl)-dithiocarbamate (23,6 g) prepared according to U.S. Pat. No. 4,064,242, absolute ethanol (500 cc) and hydrazine hydrate (5.6 g) is heated under reflux for 2 hours 30 minutes. It is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in diethyl ether (100 cc). After filtration and drying, 4-(2,2-dimethyl-dioxolan-4-yl-methyl)-thiosemicarbazide (15.2 g) is obtained in the form of a cream-coloured solid melting at 145° C.