Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:53][C:54]1[CH:63]=[C:62]2[C:57]([C:58](O)=[C:59]([C:65]3[CH:70]=[C:69]([CH3:71])[CH:68]=[C:67]([CH3:72])[CH:66]=3)[C:60](=[O:64])[NH:61]2)=[CH:56][C:55]=1[N+:74]([O-:76])=[O:75]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:58]1[C:57]2[C:62](=[CH:63][C:54]([Cl:53])=[C:55]([N+:74]([O-:76])=[O:75])[CH:56]=2)[NH:61][C:60](=[O:64])[C:59]=1[C:65]1[CH:66]=[C:67]([CH3:72])[CH:68]=[C:69]([CH3:71])[CH:70]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCO
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one (13.5 g in 600 mL of N,N-dimethylformamide) was added 9.2 g of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester and 14 g of triphenylphosphine followed by 10.4 mL of diisopropyl azodicarboxylate and the mixture stirred at room temperature. After 24 hours, the solvents were removed in vacuo and the residue resolvated in methylene chloride, washed with water and purified by flash chromatography on silica gel (hexane:ethyl acetate, 90:10; then methylene chloride:ethyl acetate, 95:5) to give the title compound (13.2 g).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[CH2:11][NH2:12])[CH2:2]1)[CH2:8]2.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[CH2:11][NH:12][C:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: NCC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC1CN(C3)C2)c1ccc2[nH]ccc2c1

Procedure:
The product of Example 1B was reacted with indole-5-carboxylic acid, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-di(methylamino)pyridine in pyridine as described in Example 3 to afford the title compound: 1H NMR (methanol-d4, 500 MHz) δ 1.82-1.89 (m, 2 H), 1.96 (br s, 3 H), 2.22-2.28 (m, 2 H), 2.31 (t, 1 H), 3.31-3.36 (m, 2 H), 3.41-3.47 (m, 2 H), 3.60-3.66 (m, 2 H), 6.54 (dd, J=3.20, 0.76 Hz, 1 H), 7.22-7.28 (m, 1H), 7.32 (d, J=3.05 Hz, 1 H), 7.42 (d, J=8.54 Hz, 1 H), 7.60-7.62 (m, 1 H), 7.64-7.70 (m, 1 H), 8.11 ppm (d, J=1.22 Hz, 1 H); MS (ESI) m/z 310 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1C=CC=C[CH:3]=1.ICCC.[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][N:26]([CH2:1][CH2:2][CH3:3])[C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccccc1
Solvent: CCCI
Product: CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 60 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodopropane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 60% yield: 1H NMR (300 MHZ, CDCl3) δ 4.18 (q, J=7.2 Hz, 2H), 4.07-3.94 (m, 2H), 3.53-3.48 (m, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.52 (s, 3H), 1.58-1.46 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H); MS (ES+) m/z 298.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH2:49][C:50]([F:52])([F:51])[F:53])(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC(F)(F)F)c(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NCC(F)(F)F)c(F)cc2Cl)CC1
Yield: 42 %

Procedure:
8.792 g (19.7 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 6.59 g (19.7 mmol) 2-chloro-5-[(2,2,2-trifluoroethylamino)sulfonyl]-4-fluorobenzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 1N methanolic ammonia in ethyl acetate in ethyl acetate. 6.31 g obtained (42% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.18-9.25 (br, 1H), 7.75-7.94 (m, 2H), 7.35-7.52 (m, 3H), 7.22-7.28 (m, 2H), 7.04-7.15 (m, 3H), 4.45-4.56 (m, 1H), 3.80-4.00 (m, 3H), 3.20-3.43 (m, 6H), 2.99-3.07 (m, 1H), 2.48-2.52 (m, 3H), 2.32-2.41 (m, 2H), 1.97-2.29 (br, 2H), 1.74-1.91 (m, 8H), 1.59-1.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])[C:2]([Cl:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)[CH3:20]
Reactant: CCO
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(N)(=O)=O)c1
Reaction time: 3 h

Procedure:
A solution of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g) in dry ethanol (250 ml) was saturated with gaseous hydrogen chloride. The reaction mixture was allowed to ware during the inlet of the hydrogen chloride. After standing for 3 hours, the solvent was removed by evaporation in vacuo. The residue was dissolved in a mixture of diethyl ether and dilute sodium hydrogen carbonate. The organic layer was separated, washed with water and dried. The diethyl ether was distilled off, and the residue was recrystallized from dry ethanol, yielding the ethyl-4-chloro-3-nitro-5-sulphamyl-benzoate with a melting point of 154°C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:61])([CH3:60])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([N:37]2[CH2:43][CH:42]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)[CH:17]=1>CN(C=O)C.O>[CH3:59][Si:56]([CH3:58])([CH3:57])[CH2:55][CH2:54][O:53][CH2:52][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:60])[CH3:61])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([N:37]2[CH2:38][CH:39]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:42]([CH2:41][CH2:40]3)[CH2:43]2)[C:17]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NBS (64 mg, 0.36 mmol) was added to a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (249 mg, 0.33 mmol) in DMF (6 mL). After stirring at room temperature for 1 h, the mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.66 Min (5 min run, UV254nm). Mass calculated for M+H 836.3, observed m/z 836.06 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:34]([C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[O:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[N:18]([S:34]([C:37]3[CH:53]=[CH:52][C:40]([O:41][CH2:42][C:43]([NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)=[O:44])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)Nc2ccccn2)cc1
Yield: 71.7 %

Procedure:
2-[[ [3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) dissolved in 20 ml of dichloromethane and 0.2 ml of triethylamine was added to 170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide. The reaction mixture was washed with water. Organic layer was dried over anhydrous magnesium sulfate, and evaporated. Residual material was lyophilized to give 237 mg of the titled product. M.P. 78-81° C.
Reaction SMILES: [O:1]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/I)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li:22])CCC>CCCCCC>[O:1]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/[Li:22])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCCCCC(/C=C/I)O[Si](C)(C)C(C)(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
On the other hand, 442 mg (1.2 mmol) of 3-t-butyldimethylsiloxy-1-iodo-trans-1-octene was added to 2 ml of anhydrous hexane, and 1 ml (1.2 mmol) of a 1.2 M hexane solution of n-butyllithium was added. The mixture was stirred at -78° C for 30 minutes in an atmosphere of nitrogen to afford an anhydrous hexane solution of 3-t-butyldimethylsiloxy-1-lithio-trans-1-octene. The resulting solution was added dropwise to the anhydrous diethyl ether solution of copper pentylide prepared previously, and the mixture was stirred at -78° C for 30 minutes in an atmosphere of nitrogen to afford a solution of an organic copper lithium compound of the following formula ##STR20##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:10]=2)[CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: COc1ccccc1-c1nnc2ccc(Br)cn12
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1-c1nnc2ccc(-c3ccc(C)cc3)cn12
Yield: 86.3 %

Procedure:
To a solution of 6-bromo-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.329 mmol) in toluene (20 mL) and water (5 mL) was added 4-methylphenylboronic acid (67.1 mg, 0.493 mmol), Pd(PPh3)4 (18.4 mg, 0.016 mmol) and Cs2CO3 (55.3 mg, 0.658 mmol), and the reaction mixture was refluxed under Argon overnight. The mixture was filtered and the filtrate was washed with water (50 mL×2), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give the title compound (89.5 mg, 50.6% yield) as yellow solids. 1H NMR (DMSO-d6): 8.09 (m, 1H), 7.93 (dd, J=9.6 and 0.9 Hz, 1H), 7.77 (d, J=9.6 and 1.8 Hz, 1H), 7.64-7.58 (m, 4H), 7.33-7.28 (m, 3H), 7.19 (t, J=7.2 Hz, 1H), 3.85 (s, 3H), 2.35 (s, 3H). MS: m/z 316.2 [M+H+].
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:28])=[O:27])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CS(=O)c1ccc(Br)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CS(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of 4-bromophenylsulfinylmethane, 177 mg (9%) of the expected sulfoxide compound, with a melting point of 121°-122° C., were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[C:16]1([CH3:30])[CH:21]=CC(S(OCC(=C)C)(=O)=O)=C[CH:17]=1.C[O-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH2:21][C:16](=[CH2:17])[CH3:30])([O-:3])=[O:2]
Reactant: C=C(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(C)COc1ccc(CC(=O)OC)cc1[N+](=O)[O-]

Procedure:
A mixture of 2.11g of methyl 3-nitro-4-hydroxyphenylacetate, 2.27g of methallyl p-toluenesulfonate was refluxed for one hour in 60ml of methanol containing natrium methoxide (natrium 0.25g). The reaction mixture was concentrated under reduced pressure and ethyl acetate and water were added to the residue. The ethyl acetate layer was isolated, and washed with water. After the extract was dried over magnesium sulfate, the solvent was distilled off and the residue was recrystallied from methanol to give the object compound having m.p. 30°- 31.5° C in a yield of 1.98g (74%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:16][CH3:17])([O:14][CH3:15])[CH:10]([OH:18])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH:10]([O:18][CH3:21])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(Cc2ccccc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b, 5.5 g, 22 mmol) from Example 1 in 30 ml of dimethylformamide was added slowly to a stirred suspension of sodium hydride (0.81 g, 27 mmol, 80% oil suspension) in 100 ml of dimethylformamide. The reaction mixture was warmed to 60° C. for 2 hours, then cooled to 0° C. whereupon methyl iodide (3.8 g, 27 mmol) was slowly added to the mixture. The reaction mixture was stirred overnight at room temperature then quenched with 10 ml of 10% sodium hydroxide solution. The reaction mixture was concentrated under vacuum, the residue slurried in 300 ml of water and the aqueous mixture extracted with 3×100 ml of ether. The combined organic layers were dried over magnesium sulfate, concentrated under vacuum, then purified by column chromatography (alumina; ethyl acetate/hexane; 2.5:1) to yield the intermediate 1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 3.77 g, 64.6%, Rf 0.63).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]#[CH:28]>S1(CCCC1)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:28][C:27]#[CH:26])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1
Reactant: COc1cc(O)ccc1C1=NC2=CCNC(=O)C2=N1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: C#CCOc1ccc(C2=NC3=CCNC(=O)C3=N2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of 2-(2-methoxy-4-hydroxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one was suspended in 30 ml of sulfolane, 1.41 g of potassium carbonate were added, and the mixture was stirred at room temperature. After 15 minutes and again after one hour, 0.9 ml of propargyl bromide was added, and the mixture was then stirred for another 1.25 hours. The solvent was substantially evaporated in vacuo, and the residue was stirred with methylene chloride. After the precipitate had been filtered off and washed with water, the product contained in the organic phase was purified on a silica gel column (eluant: methylene chloride/ethanol 1:0 to 1:0.03). The product crystallized with half a mol of ethanol.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
680 mg of triethylamine was added to a solution of 1.0 g of 1-(3-aminopropyl)-4-(diphenylmethylene)-piperidine (prepared as described in Preparation 15') in 10 ml of methylene chloride at room temperature; a solution of 680 mg of acetyl chloride in 2 ml of methylene chloride was then added dropwise to it at -10° C., after which the mixture was stirred at the same temperature for 5 minutes. Methylene chloride was then added to the mixturem, which was then washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 1.14 g (a quantitative yield) of the title compound as an oil.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])(=[O:3])[NH2:2].[NH2:15][NH2:16]>CO>[NH:15]([C:8]([C:7]1[CH:6]=[C:5]([S:1]([NH2:2])(=[O:4])=[O:3])[CH:14]=[CH:13][CH:12]=1)=[O:9])[NH2:16]
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 50.9 %

Procedure:
Methyl 3-sulfamoylbenzoate (110 mg, 0.511 mmol) was added to the hydrazine (32.8 mg, 1.022 mmol) in methanol and refluxed for 8 h at 65° G. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (5% methanol/DCM) to yield the 3-(hydrazinecarbonyl)benzenesulfonamide (57 mg, 0.260 mmol, 50.8% yield) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.32 (m, 1H), 8.04 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.63 (t, 1H, J=8.0 Hz). Mass [M+H]+: 216.0
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1.Br[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]>ClCCl>[C:17]1([CH:15]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCNC1
Reactant: CC(Br)c1ccccc1
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCC[C@H](C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
In a flask, dichloromethane (0.432 mL) was added to (S)-tert-butyl piperidine-3-carboxylate (0.020 g, 0.108 mmol). At 0° C., (1-bromoethyl)benzene (0.030 g, 0.162 mmol) was added to the reaction. The solution was allowed to stir from 0° C. to room temperature for 3 hrs. The reaction was quenched using water (1 mL) and extracted using dichloromethane (3×1 mL). The extractions were combined and dried using sodium sulfate. The extracts were concentrated in vacuo, and the crude product was progressed to the next step without further purification.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([F:15])[CH:7]=1>C(O)C.[Cl-].[Na+].O>[F:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:6]([CH2:5][S:2][CH3:1])[CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc(F)cc(CCl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCc1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
Sodium methanethiolate (1.22 g; 17.4 mmol) was added in three portions to a stirred solution of 1-(chloromethyl)-3-fluoro-5-nitrobenzene (3.00 g; 15.8 mmol, HE Chemical) in ethanol (33 mL) at 0° C. The ice bath was removed and the batch was stirred at room temperature for 18 hours. Further sodium methanethiolate (0.33 g; 4.7 mmol) was added and the batch was stirred for 5 additional hours at room temperature. The batch was diluted with brine and extracted with ethyl acetate (2×). The combined organic phases were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (3.4 g) that was used without further purification.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH2:19][CH2:18][CH2:17]3)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[CH:26](O)=O>>[CH3:26][N:20]1[C:21]2[C:16](=[CH:15][C:14]([CH:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:13])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)CCCN2
Reactant: O=CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)CCCN2C

Procedure:
Example 256 was prepared from 3-phenyl-N-[1-(1,2,3,4-tetrahydro-quinolin-6-yl)-ethyl]-acrylamide by treatment with formic acid and sodium borohydride following the general procedures described by Gribble et. al. (J. Amer. Chem. Soc., 1974, 7812).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]2)=[CH:4][CH:3]=1.[CH2:29](C([Sn])=C(CCCC)CCCC)[CH2:30]CC.CCOC(C)=O>C1(C)C=CC=CC=1>[CH:29]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]2)=[CH:4][CH:3]=1)=[CH2:30]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nccc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Aryl bromide from Step 1 was dissolved in toluene (about 0.15 mM solution) and treated with tributylvinyltin (1.5 eq) and [Ph3P]4Pd(0) (0.05 eq). The reaction mixture was stirred at 100° C. under N2 atmosphere for 2 h. After cooling to RT, the reaction mixture was poured into EtOAc and washed with brine. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, PE/EtOAc 8/2 v/v as eluent) to give the title compound as a viscous oil. MS (ES+) C22H26N2O5 requires 398. Found: 399 (M+H+).