Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=2[N:12]=1.[CH3:21][O:22][C:23]([C:25]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24]>C(O)C>[CH3:21][O:22][C:23]([C:25]1([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:15]3[C:14]4[CH2:18][CH2:19][CH2:20][C:13]=4[N:12]=[C:11]([Cl:10])[N:16]=3)=[CH:33][CH:34]=2)[CH2:26][CH2:27][CH2:28]1)=[O:24]
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Temperature: 10 °C
Yield: 61.8 %

Procedure:
Diisopropylethylamine (45.9 mL, 264.55 mmol) was added slowly to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (10 g, 52.91 mmol) and 1-(4-amino-phenyl)-cyclobutanecarboxylic acid methyl ester (13.015 g, 63.49 mmol) in anhydrous ethanol (100 mL) under stirring at 10° C. Thereafter, the mixture was heated at reflux for 48 hours and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel) to afford the title compound as a light yellow solid (11.7 g, 62% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC1(C)OC[C@@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC[C@@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 13 h
Yield: 100.1 %

Procedure:
In N,N-dimethylformamide (40 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.48 g, 8.34 mmol) and (4R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (3.20 g, 12.51 mmol). Cesium carbonate (3.81 g, 11.68 mmol) was added to the solution and the mixture was stirred at 50° C. for 13 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 2.55 g (100%) of the title compound in the form of a light yellow oily product.
Reaction SMILES: [C:1]([C:4]1[N:8](CC2C=CC(OC)=CC=2)[C:7]([SH:18])=[N:6][N:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]([C:4]1[N:8]=[C:7]([SH:18])[NH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(Cn2c(S)nnc2C(N)=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1n[nH]c(S)n1
Yield: 99.1 %

Procedure:
3-Carbamoyl-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol (2.0 g., 0.007 mole), trifluoroacetic acid (8 ml.) and anisole (2 ml.) were heated at 70° C. for 3.5 hours. At this point, most of the trifluoroacetic acid present was removed by means of evaporation under reduced pressure and the residue was subsequently triturated with diethyl ether. The resulting solid was then filtered, washed with diethyl ether and subsequently dired in vacuo at 50° C. to give pure 3-carbamoyl-1,2,4-triazole-5-thiol (1.0 g., 91% yield), m.p. 276°-278° C. The infrared absorption spectrum was identical to that of a reference sample prepared as described in Example XVI, Part C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=2)=[CH:25][N:24]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]3[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=3)=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: CCO
Solvent: c1ccncc1
Product: Cn1ccc(Cc2cnc(NCCCOc3cccc(CN4CCCCC4)c3)[nH]c2=O)cc1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.12 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.11 g) were refluxed in ethanol (8 ml) for 20 hours. As the reaction was incomplete the ethanol was replaced by pyridine (8 ml) and the solution refluxed for a further 6 hours. The reaction mixture was evaporated under reduced pressure and the residue was subjected to medium pressure chromatography on silica gel (eluting with 10% methanol/90% chloroform) to afford the title compound. This was treated with dilute ethanolic HCl to afford material which was recrystallised from isopropanol/ether to afford 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one dihydrochloride (0.85 g), m.p. 164°-167° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid t-butyl ester according to conditions described in general procedure C. Mp: 131-133° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.38 (s, 9 H), 3.27-3.34 (m, 8H), 3.50 (bs, 4 H), 3.77 (t, J=4.38 Hz, 4 H), 6.24-25 (m, 1 H), 7.04 (d, J=11.3 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.56-7.63 (m, 3 H), 7.85 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.8 Hz, 1 H), 8.29-8.30 (m, 1 H), 10.48 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O=[Pt]=O.C(O)C>[CH:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C1(C2CCCCC2)CC1
Yield: 57.8 %

Procedure:
To 1-phenyl-cyclopropanecarboxylic acid (0.500 g) in acetic acid (2 mL) was added Adams catalyst (0.050 g) in ethanol (0.3 mL). The reaction was left to stir for 48 hours under 5 bar of hydrogen. The reaction was filtered, washing with ethanol (10 mL) and water (10 mL). The resulting solid was collected by filtration and subsequently washed with water (10 mL) to afford the sub-titled compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:17]([NH:25][C:26]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:4][CH:3]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl N-(4-aminobenzyl)carbamate (6.00 g, 27.0 mmol) in anhydrous THF (50 ml) was added benzoylisothiocyanate (4.43 g, 27.0 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo to yield 100% (10.4 g) of the protected thiourea as a yellow solid: m.p. 161-163° C.; 1H-NMR (CDCl3) δ 1.45 (9H, s), 4.33 (2H, d), 4.85 (1H, broad), 7.34 (2H, d), 7.60 (5H, m), 7.90 (2H, d), 9.13 (1H, s), 12.58 (1H, s); 386 (ESMS, MH+).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:1][C@@H:2]1[C@@H:7]([CH2:8][NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNCc2ccccc2)[C@@H](O)C1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A mixture of 1,1-dimethylethyl(3R-trans)-3-hydroxy-4-[[(4-methylphenyl)-sulfonyl]oxymethyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c-I)] (0.03 mol) and benzylamine (0.1 mol) in THF (250 ml) was stirred for 16 hours at 125° C. (autoclave). The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and an aqueous K2CO3 solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE, yielding 5.3 g of 1,1-dimethyl-ethyl (3R-trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate (intermediate 60) ([α]20,D=−68.65° (c=23.16 mg/S ml in CH3OH); mp. 91° C.).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].CO.S(=O)(=O)(O)O>O>[F:23][C:15]([F:24])([C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])[CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)COCCOCCOC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Then, 17.4 g (0.047M) of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above), 35 ml of methanol, 18 ml of water and 2.2 ml of concentrated sulfuric acid were placed in a 100 ml-reaction vessel, followed by stirring for 2 hours at room temperature. The reaction mixture was poured into water and saturated with common salt. The saturated reaction mixture was subjected to extraction with ethyl acetate, washed with saturated common salt water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain a residue. The residue was subjected to reduced-pressure distillation to obtain 6.4 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecanol (b.p.: 86°-87° C./6 mmHg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]3)[C:4]=2[O:3][CH2:2]1.[F:24][C:25]1[CH:26]=[C:27]([NH:31]N)[CH:28]=[CH:29][CH:30]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]4[N:31]([C:27]5[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=5)[N:20]=[CH:19][CH:18]=4)=[N:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OCO3)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2cccc3c2OCO3)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 1-Benzo[1,3]dioxol-4-yl-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-14) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=377.2 (M+H)+
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][CH:8]=[O:9].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CN(C=O)C.C(N(CC)CC)C.[Cu]I.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][CH:8]=[O:9])([CH3:15])[CH3:14]
Reactant: O=CNc1ccsc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1sccc1NC=O
Yield: 95.3 %

Procedure:
The product from step A (37.8 g) was dissolved in a mixture of DMF (500 ml) and triethylamine (50 ml). CuI (1.4 g) and bis(triphenylphosphino)palladiumdichloride (5.2 g) were added under nitrogen and after 15 minutes ethinyl trimethylsilane (22 g) was added dropwise. After 6 hours the solvents were removed under vacuum and the residue was chromatographed on silica gel (hexane:ethyl acetate 2:1) to yield 2-(trimethylsilylethinyl)-3-formamido-thiophene (31.78 g) (m.p. 87-93° C.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6](C)(C)[CH2:5][C:4]=2[N:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16]>C(N(CC)CC)C.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>[C:17]1([C:15]#[C:16][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1CCCc2nc(C#Cc3ccccc3)ccc21
Yield: 14.7 %

Procedure:
To a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one (0.2 g, 1.1 mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium (0.02 g, 0.062 mmol). The mixture was heated at reflux for 3 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.04 g, 15%).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17]Br)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C([Mg]Br)C.[Mg].BrCC.[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:29][Mg]Cl>C1COCC1>[CH3:14][C:6]1[C:7]([OH:13])=[C:8]([CH3:12])[C:9]2[CH2:10][CH2:11][C@:2]([CH2:16][CH2:17][CH2:41][C@@H:39]([CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:34][CH2:33][CH2:32][CH:28]([CH3:29])[CH3:27])[CH3:42])[CH3:40])([CH3:1])[O:3][C:4]=2[C:5]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Reactant: CC(C)CCCC(C)CCCC(C)C[Mg]Cl
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 86 %

Procedure:
3.13 g (10 millimoles) of (2RS)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were dissolved in 10 ml of absolute THF. A solution of ethyl-magnesium bromide which had been prepared by reacting 0.25 g (10.3 millimoles) of magnesium in 3 ml of THF with a solution of 1.1 g (10.0 millimoles) of bromoethane in 5 ml of THF and stirring for 1 hour at +40° C. was added dropwise to the above solution at -20° C. The resulting reaction mixture was stirred for 1 hour at -20° C. and then there were added to it the (2RS,6RS)-2,6,10-trimethyl-1-undecyl-magnesium chloride solution prepared in Example 2a, followed by 0.7 ml of an 0.5-molar solution of di-lithium tetrachlorocuprate in absolute THF. The batch was then stirred for 3 hours at -20° C. and 16 hours at room temperature. The reaction mixture was worked up as described in Example 1c and 3.7 g of α-tocopherol were isolated by bulb tube distillation at 220° C./0.2 mbar. This corresponds to a yield of 86% of theory.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21](Cl)=[O:22]>ClCCl>[Br:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:22]
Reactant: CC(Br)/C=C/C(=O)Cl
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Product: CC(Br)/C=C/C(=O)N1CCN(c2ccnc3ccccc23)CC1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
4-piperazin-1-ylquinoline (21.3 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (0.5 ml), TEA (20.9 μl, 1.5 mmol) followed by (E)-4-bromopent-2-enoyl chloride (29.6 mg, 0.15 mmol) were added, the mixture was shaken for 10 minutes, diluted with dichloromethane, washed with 5% sodium bicarbonate solution, water and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 7 mg of a solid (0.019 mmol, 19%).
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][SH:25].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][S:25][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: CN(C)CCS
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CN(C)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
The title compound of Step 10 (1.5 g, 5.95 mmol) was dissolved under argon in methanol (22 mL). To this solution was added 2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed on a rotary evaporator and then the residue was purified by flash chromotography on silica gel, eluting with 20:1 CH2Cl2 :MeOH to give the pure title compound (0.5 g, 24% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C21H27NO2S+0.2H2O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60; N, 3.98.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@:12]2([CH3:23])[O:16][C:15]3=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]3[CH2:13]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C@:12]3([CH3:23])[O:16][C:15]4=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]4[CH2:13]3)[CH2:7][CH2:6]2)=[O:4])=[CH:27][CH:26]=1
Reactant: C[C@]1(CN2CCN(C(=O)CCl)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Sc1ccc(Cl)cc1
Product: C[C@]1(CN2CCN(C(=O)CSc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 20.3 %

Procedure:
Using a mixture of (S)-2-chloro-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone prepared in Example 420 (300 mg, 0.87 mmol) and 4-chlorothiophenol (190 mg, 1.32 mmol) gave (S)-2-(4-chlorophenylsulfanyl)-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone (80 mg, yield 20%) as a white powder in the same manner as in Example 421.
Reaction SMILES: [H][H].[CH2:3]([N:10](CC1C=CC=CC=1)[C:11]1[N:12]=[CH:13][CH:14]=[C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])[NH:17][C:16]=12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>[Pd].C(O)C>[CH2:3]([NH:10][C:11]1[N:12]=[CH:13][CH:14]=[C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[O:21])[NH:17][C:16]=12)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccncc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(NCc1ccncc1)c1cc2ccnc(NCc3ccccc3)c2[nH]1
Yield: 24.6 %

Procedure:
Hydrogen (1 atm, balloon) was applied to a slurry of 7-(dibenzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Example 41) (69 mg, 0.15 mmol), 10% palladium on carbon (wet, 100 mg) and HCl (saturated solution in 2-propanol, 5 M, 0.5 mL) in ethanol (4.5 mL) at room temperature for 3 h. The slurry was filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The two layers were separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:1 to 1:2 hexanes/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7-(benzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (13.2 mg, 24%) as colorless crystals: Rf 0.42 (silica gel, 20:80 methanol/ethyl acetate); mp 199-200° C. (recrystallized from hexanes/ethyl acetate); 1H NMR (300 MHz, CD3OD) δ4.63 (2H, s), 4.69 (2H, s), 6.91 (1H, d, J=6.0 Hz), 7.05 (1H, s), 7.22-7.43 (7H, m), 7.55 (1H, d, J=6.0 Hz), 8.48 (2H, d, J=6.0 Hz); ESI MS m/z 358 [C21H19N5O+H]+; HPLC (Method A) >99% (AUC), tR=13.2 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1
Reactant: CNc1nnc(Cl)cc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-yl]-methyl-amine (95 mg, 355 μmol) in dichloromethane (5 mL) was added 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (95.2 mg, 355 mmol) and 2-bromo-1-ethylpyridinium tetrafluoroborate (117 mg, 426 μmol, CAS RN 878-23-9) and N-ethyldiisopropyl-amine (91.7 mg, 124 μL, 710 μmol). The reaction mixture was stirred at room temperature for 72 hours and then poured on 30 mL 10% aqueous bicarbonate solution and 30 mL dichloromethane and the layers were separated. The aqueous layer was extracted a second time with 30 mL dichloromethane. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colorless solid (63 mg, 34.3%). MS (ESI+): m/z=518.056 ([M+H]+).