Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9]([OH:31])[C@H:10]1[O:15][C@H:14]([O:16][C@H:17]2[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20](O)[O:19][C@@H:18]2[CH2:26][OH:27])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]1[OH:30].N1C=CC=CC=1.C(O)C>O>[OH:24][CH:21]([CH:20]1[NH:2][CH:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]1)[CH:22]([OH:23])[CH:17]([O:16][CH:14]1[O:15][C@H:10]([CH2:9][OH:31])[C@@H:11]([OH:30])[C@H:12]([OH:29])[C@H:13]1[OH:28])[CH:18]([OH:19])[CH2:26][OH:27]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=C(O)C1CSC(C(O)C(O)C(OC2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C(O)CO)N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
17.56 Grams (100 mmol) of cysteine hydrochloride and 34.20 g (100 mmol) of maltose were dissolved in 35 ml of pure water, 8.36 ml (100 mmol) of pyridine was then added thereto, and the resulting solution was stirred at room temperature for 72 hours. 300 Milliliters of ethanol was added to the stirred solution, and the solution was left to stand in a refrigerator, whereby a paste-like precipitate was formed. The solvent was removed by decantation, and the precipitate was dissolved in 100 ml of water. After the insoluble matters were removed by filtration, the remaining solution was condensed to about 30 ml. Ethanol was continuously added to the condensed solution until a precipitate was about to appear, and the solution was then left to stand in a refrigerator overnight. The produced crystals were collected by filtration. The crystals were then dissolved in water again, the insoluble matters were removed by filtration, the resulting solution was condensed, and ethanol was added to the solution to cause recrystallization. The produced crystals were collected by filtration and dried under reduced pressure to obtain 2.2 g of a white powder (molar yield based on cysteine: 4.9%).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC([O-])=O)C=CC=1OC.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:27].C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH3:27]
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1ccc(C(=CC(=O)[O-])c2ccc(OC)c(OC)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.35 g (96%) of a mixture of the E and Z isomers as a white solid: mp 74-77° C.; 1H NMR (CDCl3) δ 7.50-7.24 (m, 10H), 7.07-6.75 (m, 6H), 5.67 (s, 1H), 5.60 (s, 1H), 4.15-3.95 (m, 4H), 3.92 (s, 3H), 3.89 (s, 3H), 1.50-1.36 (m, 6H); 13C NMR (CDCl3) δ 162.8, 162.7, 151.4, 150.9, 148.1, 147.1, 147.9, 139.3, 137.1, 131.3, 130.2, 129.9, 129.5, 129.3, 128.6, 128.5, 128.4, 123.1, 122.0, 118.3, 118.2, 113.9, 112.5, 110.9, 93.3, 92.9, 64.4, 55.9, 55.9, 14.6; Anal. Calcd for C18H17NO2. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.14; H, 6.06; N, 4.75.
Reaction SMILES: [CH2:1]([C:3]1C=C[C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=CC=C[N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:1][N:28]=2)[CH:10]=1
Reactant: ClCc1ccccn1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ccccn2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-chloromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][N:16]([C:18]([N:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH3:21])=[O:19])[CH:17]=2)=[CH:9][CH:8]=1>O1CCOCC1>[CH:22]1([N:20]([CH3:21])[C:18]([N:16]2[CH:17]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:4][S:1](=[O:3])(=[O:2])[NH2:5])=[CH:8][CH:9]=3)[N:14]=[CH:15]2)=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NS(N)(=O)=O
Reactant: CN(C(=O)n1cnc(-c2ccc(N)cc2)c1)C1CCCCC1
Solvent: C1COCCO1
Product: CN(C(=O)n1cnc(-c2ccc(NS(N)(=O)=O)cc2)c1)C1CCCCC1
Yield: 6 %

Procedure:
Sulfamide (0.089 g, 0.922 mmol) was added to a stirred suspension of 4-(4-aminophenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (0.250 g, 0.838 mmol) in dioxane (2 mL) at room temperature. The suspension was heated at reflux for 4 h to give a clear solution, whereupon more sulfamide (0.089 g, 0.922 mmol) was added and the mixture was heated at reflux for a further 2.5 h. The solvent was removed and the brown residue was purified by chromatography (silica, dichloromethane/methanol, 1%, 2%, 5%). Homogenous fractions were pooled and evaporated. The residue was triturated with ethyl acetate and the colourless solid that formed was removed by filtration. The filtrate was evaporated and purified again by preparative TLC (silica, dichloromethane/10% methanol). The product was extracted from the silica with a mixture of ethyl acetate/10% methanol. Evaporation of the solvent gave a clear oil, that was triturated with a mixture of ethyl acetate and methanol to give the product as an off-white solid (19 mg, 6%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[O:5][C:4](=[O:19])[CH:3]=1.CCN(CC)CC.[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:5][C:4](=[O:19])[C:3]=1[CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:30]([CH3:31])[CH:29]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(CC2=C(O)CC(CCC(C)C)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(3-methylbutyl)-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), 3-methylbenzoyl chloride (0.15 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.51 g, 8.1 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 0.5% MeOH in CH2Cl2) to provide a solid (0.252 g, 53°-55° C.). 1H NMR (400 MHz, DMSO-d6) δ 7.376-7.244 (m, 5 H), 6.915 (t, 1 H, J=7.5 Hz), 6.831 (d, 1 H, J=7.5 Hz), 6.549 (d, 1 H, J=7.5 Hz), 6.509 (s, 1 H), 3.369 (AB, 2 H, JAB =14.4 Hz), 3.112 (AB, 2 H, JAB =17.5 Hz), 2.088 (s, 3 H), 1.962 (m, 2 H), 1.416-1.333 (m, 1 H), 1.152-1.061 (m, 1 H), 0.898-0.726 (m, 7 H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)C[C@@H]1CCCCOC1
Yield: 83 %

Procedure:
Above tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-ylcarbamate was hydrogenated under H2 (40 psi), catalyzed by 10% Pd/C, in MeOH for 1 h. The catalyst was filtered off and concentrated to give tert-butyl (S)-1-amino-3-((S)-oxepan-3-yl)propan-2-ylcarbamate (55 mg, 83% over 2 steps). MS ESI +ve m/z 273 (M+H).
Reaction SMILES: [CH2:1]([C@@H:7]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.O=[Pt]=O>[CH2:1]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC1CC(=O)[C@@H](CCCCCC)C(=O)O1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H]1C[C@H](O)[C@H](CCCCCC)C(=O)O1
Reaction time: 12 h

Procedure:
M)c) 8 g of an isomer mixture of tetrahydro-3-hexyl-4-oxo-(R)-6-undecyl-2H-pyran-2-one were dissolved in 2 l of ethyl acetate and 3 g of PtO2 were added. The mixture was then hydrogenated (50 bar) for 12 hours. The catalyst was filtered off and the solution was evaporated. After recrystallization there were obtained 7 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one, m.p. 108°-109° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3N3CCCC3)nc2c1
Temperature: 60 °C
Yield: 101.1 %

Procedure:
A mixture of 0.31 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.21 g of pyrrolidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 60° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.37 g of 2-[3-(pyrrolidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 53”).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:10]=1
Reactant: COc1cccc(-c2cnc3ccccc3c2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1cccc(-c2cnc3ccccc3c2)c1
Yield: 85 %

Procedure:
The compound is prepared by reaction of 3-(3-methoxyphenyl)quinoline (101 mg, 0.43 mmol, 1 eq) with aluminum trichloride (341 mg, 2.57 mmol, 6 eq) according to method F. Purification by preparative thin-layer chromatography with dichloromethane/methanol 95/5 (DC plates coated with 1 mm thick coating) yields the desired product in a yield of 85%, 81 mg.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[N:18]=[C:17]([C:19]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[O:22][C:21]([CH3:32])([CH3:31])[CH:20]=2)[CH:16]=[CH:15][CH:14]=1>ClCCl>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[O:22][C:21]([CH3:32])([CH3:31])[CH:20]=2)[N+:18]=1[O-:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=C(c2cccc(N)n2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)C=C(c2cccc(N)[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 3 h
Yield: 22.2 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 554 mg of 4-(6-amino-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile in 10 ml of dichloromethane and the mixture was stirred for 3 hours. The mixture was then washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:4) for the elution to give a solid which was triturated with dichloromethane and recrystallized from isopropanol. There were obtained 130 mg of 2-amino-6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 241°-242° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[NH:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:10])[CH2:14]1
Reactant: O=C(NCC1CN(C(=O)OCc2ccccc2)CCO1)Nc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NCC1CNCCO1)Nc1ccccc1
Temperature: 22 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
A suspension of 10% palladium on carbon (1.5 g) and Intermediate 6 (3.2 g) in ethyl acetate (250 ml) was stirred vigorously under hydrogen at 1 atmosphere and 22° C. for 20 h. The catalyst was filtered off and the volatiles were removed in vacuo. The procedure was repeated with a further portion of the catalyst (1 g) for a further 24 h before filtration and solvent evaporation in vacuo. Purification of the residue by Biotage flash chromatography on a 90 g silica cartridge, eluting with 100:8:1 dichloromethane/ethanol/0.880 ammonia solution, gave the title compound as a colourless oil (1.6 g). LC/MS (System A) Rt 1.39 min, Mass Spectrum m/z 236 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:28]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[CH:11][N:12]=[C:13](Cl)[C:8]2=[N:7][C:6]=1[CH2:15][CH3:16])=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[CH:11][N:12]=[C:13]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][C:22]=3[Cl:24])[C:8]2=[N:7][C:6]=1[CH2:15][CH3:16])=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCc1nc2c(Cl)nccn2c1C(=O)OC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1C(=O)OC
Yield: 77.4 %

Procedure:
8-Chloro-2-ethylimidazo[1,2-a]pyrazine-3-carboxylic methyl ester (0.92 g, 3.8 mmol) synthesized in Reference Example 1 was dissolved in a mixed solvent of toluene (32 mL) and methanol (8 mL), then 2,4-dichlorobenzeneboronic acid (1.49 g, 7.8 mmol) and tetrakistriphenylphosphine palladium complex (230 mg, 0.2 mmol) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, and purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (1.03 g) as a pale yellow crystals.
Reaction SMILES: [CH2:1]1[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].[H-].[Na+]>CN(C)C=O>[S:3]1[CH2:2][CH2:1][C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:12])[S:4]1
Reactant: O=C(O)CCCC[C@H]1CCSS1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)CCCC[C@H]1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
300 mg of (S)-α-lipoic acid were dissolved in 6 ml of anhydrous dimethylformamide, and 276 mg of N,N'-carbonyldiimidazole and 1 ml of anhydrous dimethylformamide were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour and 30 minutes. At the end of this time, 162 mg of methanesulfonamide and 74 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the reaction mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour and then left to stand for 2 days. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1:1 and 3:1 by volume mixtures of ethyl acetate and hexane as eluent. It was then recrystallized form a 1:2 by volume mixture of ethyl acetate and hexane, to obtain 154 mg of the title compound, melting at 91° C. to 92° C.
Reaction SMILES: C(NC1C=C([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)C=CC=1Cl)(=O)C1C=CC=CC=1.C[C@H]1O[C@@H](C)CNC1>>[C:18]([NH2:17])(=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Agent: C[C@@H]1CNC[C@H](C)O1
Product: NC(=O)c1cccnc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylmorpholine (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(2,6-dimethylmorpholin))nicotinamide. MS (Q1) 465.0 (M)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:32])[C:19]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][O:21][CH:22]([F:24])[F:23])=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.Br.C(O)(=O)C>O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:19](=[CH:20][O:21][CH:22]([F:23])[F:24])[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=2)=[O:32])=[CH:26][CH:27]=1
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
1.45 g (2.97 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)-3-difluoromethoxyacrylamide, 751 mg (4.46 mmol) of 48% hydrobromic acid and 15 ml of acetic acid were mixed and stirred at 80° C. for 1.5 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to give 880 mg of 2-(4-chlorophenyl)-3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]acrylamide (the present compound 1454).
Reaction SMILES: C([N:3]=[C:4]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)[CH2:17][CH2:16]1)[NH:5][CH2:6][CH:7](OC)[O:8]C)#N.Cl.N>O>[OH2:8].[NH2:3][C:4]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:25]4[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)[CH:7]=[CH:6][N:5]=1
Reactant: COC(CNC(=NC#N)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)OC
Agent: Cl
Agent: N
Solvent: O
Product: Nc1nccn1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 5 parts of N"-cyano-N-(2,2-dimethoxyethyl)-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]guanidine and 60 parts of concentrated hydrochloric acid was stirred and refluxed for one hour. Water was added and the whole was alkalized with ammonia. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1 part of N-[1-[2-(2-amino-1H-imidazol-1yl]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine monohydrate; mp. 171.4° C. (compound 60).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)[C:12]#[CH:13]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:13]#[C:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH3:10])=[CH:4][N:3]=1
Reactant: C#CC(C)c1cc(OC)c(OC)c(OC)c1
Reactant: Nc1ncc(I)c(N)n1
Product: COc1cc(C(C)C#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 89.8 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 5-(But-3-yn-2-yl)-1,2,3-trimethoxybenzene (440 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)but-1-ynyl)pyrimidine as a yellow powder (295 mg, 90%): Rf=0.29 (9:1, CHCl3:MeOH); mp=220-222° C.; 1H NMR (DMSO-d6) δ 7.85 (s, 1H), 6.75 (s, 2H), 6.28 (s, 2H), 3.99 (q, J) 6.8 Hz, 1H), 3.78 (s, 6H), 3.63 (s, 3H), 1.50 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 163.7, 152.8, 139.3, 136.0, 104.2, 104.1, 97.9, 76.2, 60.0, 60.0, 55.9, 55.8, 32.3, 24.3; Anal. (C17H20N4O3) C, H, N.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][C:28]#[CH:29].C(O)(=O)C(O)=O.CC(C)=O>CC#N>[CH2:29]([N:4]1[CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:1][CH2:2][CH2:3]1)[CH2:28][C:27]#[CH:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: C#CCCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 67.5 °C
Reaction time: 15 h

Procedure:
Charge in order, 23.7 g of CH3CN, 10 g of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, 9.2 g of K2CO3 then 8.4 g of 4-bromobut-1-yne to R1. Heat the mixture to 65-70° C. and stir the mixture at 65-70° C. for 12-18 hours. Concentrate the mixture to a total weight of 30-40 g below 50° C., then add 76 g of MTBE and 50 g of water. Stir the mixture at 20-25° C. for 30 mins then allow to stand to 30 mins Separate the aqueous. Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C. Stir the mixture at 20-25° C. for 30 mins then allow to stand for 20-30 mins at 20-25° C. Separate the aqueous layer out and wash the organics with 50 g of water. Concentrate the organic phase to 40-50 g total weight below 50° C. in R1. Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone, then add drop wise the oxalic acid/acetone solution into R1 at 20-25° C. Stir the suspension at 20-25° C. for 2-3 hours then filter. Wash the cake with 15.2 g of MTBE. Slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Again, slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Dry the cake under vacuum at 50-60° C. for 16-18 hours to provide the title compound, tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate; oxalic acid.