Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: BrCC1CC1
Reactant: CC12COCCN1c1nc(Cl)ncc1NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 131.7 %

Procedure:
2-Chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.846 g, 3.32 mmol) and (bromomethyl)cyclopropane (0.672 g, 4.98 mmol) were mixed in DMSO (5 ml). Potassium carbonate (0.918 g, 6.64 mmol) was added. The mixture was stirred for 30 minutes at room temperature and then for 2 hours at 35° C. EtOAc (40 ml) was added followed by addition of water (30 ml). Aqueous phase was separated and extracted with EtOAc (2×30 ml). The combined organic phase was washed with water (2×20 ml). The organic solution was concentrated to near dryness at which point a solid had precipitated out. EtOAc (5 ml) and hexanes (20 ml) were added and the mixture was stirred for 20 minutes. The solid was collected by filtration to afford 1.35 g product as a white solid. Concentration and crystallization of mother liquor afforded another 0.28 g of compound as second crop. 1H NMR (400 MHz, CDCl3) δ=0.34 (m, 2H), 0.46 (m, 2H), 1.13 (m, 1H), 1.39 (s, 3H), 3.21 (m, 1H), 3.55 (m, 1H), 3.66 (d, 1H), 3.77 (m, 1H), 3.85-4.02 (m, 4H), 8.20 (s, 1H)
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]#[N:12].[H-].[Na+].CCCCCC.C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[C:11]([CH:10]1[CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[CH:8][CH:7]=[C:6]12)#[N:12]
Reactant: N#CCc1cccn1CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: N#CC1CCCn2cccc21
Reaction time: 1 h

Procedure:
1-(3-Iodopropyl)pyrrol-2-acetonitrile (31 g., 0.128 moles) is dissolved in dry dimethylformanide (35 ml.) is added with stirring to a cooled (-5°) suspension of sodium hydride (50%, 7.5 g., 0.156 moles) in dry dimethylformamide (100 ml.), maintained in an atmosphere of dry nitrogen, at a rate such that the reaction temperature is maintained between -5° to +5°. When the addition is completed, stirring at this temperature is continued for 1 hour at which time the starting material is shown to be absent by t.l.c. (silica gel, hexane-ethyl acetate, 1:1). A cold, dilute solution of sodium chloride (150 ml.) is added to the reaction during 15 minutes and the product is extracted into benzene. The extract is washed with dilute sodium chloride solution (3 times), with water (once) and then it is dried over sodium sulfate. The solvent is removed in vacuo leaving an oil (21.1 g.) which is chromatographed on silica gel. The crystalline product (13.6 g., 72%) is eluted with hexane-ethyl acetate (97.5:25 and 95:5). Crystallization from hexane-acetone yields 8-cyano-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine (XIX, n is 1), m.p. 47°-49°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=O)[CH3:22])[O:7][CH:6]1Br)(=[O:3])[CH3:2].C([CH:28]1[CH:33](O)[CH:32](O)[CH:31](O)[CH:30]([CH2:37]O)O1)C=C>>[C:30]1([CH:6]2[O:7][CH:8]([CH2:19][OH:20])[CH:9]([OH:15])[CH:10]([OH:11])[CH:5]2[OH:4])[CH:31]=[CH:32][CH:33]=[CH:28][CH:37]=1.[C:12]([O:11][CH:10]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]([C:31]2[CH:30]=[CH:37][CH:28]=[CH:33][CH:32]=2)[O:7][CH:8]([CH2:19][O:20][C:21]([C:22]2[CH:5]=[CH:10][CH:9]=[CH:8][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:28][CH:37]=2)[C:31]2[CH:30]=[CH:37][CH:28]=[CH:33][CH:32]=2)[CH:9]1[O:15][C:16](=[O:18])[CH3:17])(=[O:14])[CH3:13]
Reactant: C=CCC1OC(CO)C(O)C(O)C1O
Reactant: CC(=O)OC[C@H]1OC(Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(c2ccccc2)C(OC(C)=O)C1OC(C)=O
Product: OCC1OC(c2ccccc2)C(O)C(O)C1O
Yield: 64 %

Procedure:
6-Phenyl-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol was prepared from 2,3,4,6-tetra-O-acetyl-D-mannopyranosyl bromide according to the method of Hurd and Holysz (Hurd, C. D. and Holysz, R. P., (1950). Reactions of polyacylglycosyl halides with Grignard reagents. J. Am. Chem Soc., 1950, vol 72, 1732-1738) incorporated herein by reference. This compound (2.4 g, 10 mmol) was tritylated, acetylated in the same manner as described for to 2-allyl-6-hydroxymethyl-tetrahydropyran-3,4,5-triol in Example 3 to give acetic acid 4,5-diacetoxy-6-phenyl-2-trityloxymethyl-tetrahydro-pyran-3-yl ester (3.1 g, 64%). This compound was detritylated, phosphorylated and deacetylated as described for acetic acid 4,5-diacetoxy-6-allyl-2-trityloxymethyl-tetrahydropyran-3-yl ester in Example 3 above to give 6-phenyl-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl phosphoric acid ester (22% overall yield) ESMS (−ve) 319 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([CH3:29])=[N:25][O:26][C:27]=2[CH3:28])[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([CH3:29])=[N:25][O:26][C:27]=2[CH3:28])[O:20][N:19]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C)noc2C)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 5.80 (s, 2 H), 2.91 (t, J=4.9 Hz, 2H), 2.66 (s, 3H), 2.38 (s, 3H), 1.71-1.58 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (ES) m/z 396 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1)=[O:10].[BH4-].[Na+].O.ClCCl>CO>[OH:10][CH:9]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:15][CH2:16]1)[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]ccnc1CN1CCC(C(O)Cc2ccccc2F)CC1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
After suspending 200 mg of 3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 6 ml of methanol, an excess of sodium borohydride was added while stirring at room temperature until completion of the reaction. Water was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (112 mg, 56% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CCCCBr
Product: CCCCn1ccc2cc(OC)ccc21

Procedure:
By treating in analogous manner 5-methoxy-indole with n-butyl bromide, 1-n-butyl-5-methoxy-indole is obtained (b.p.:103° -104° C., nD20 :1.5674).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Mg]Br)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[CH2:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([OH:27])[CH2:23][CH2:22][N:21]([CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[C:17]([O:16][CH3:15])[CH:18]=3)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(I)cc1Cl
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 3,4-dichloro-1-iodobenzene (9.00 g, 41.0 mmol) in tetrahydrofuran (80 mL) at room temperature, was added isopropylmagnesium bromide (40.5 mL of a 2.0 M solution in THF, 82.0 mmol) dropwise. After 2 h, a solution of 1-(3-methoxybenzyl)piperidin-4-one (9.0 g, 41.0 mmol) from Step B above in tetrahydrofuran (10 mL) was added dropwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 2 h. After 1 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL). The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (80 mL), water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (dichloromethane to 10% ethyl acetate in dichloromethane) gave 4-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (13.0, 86%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.62 (d, J=2.0 Hz, 1H), 7.43-7.38 (m, 1H), 7.36-7.30 (m, 1H), 7.25-7.21 (m, 1H), 6.96-6.90 (m, 2H), 6.84-6.77 (m, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 2.84-2.76 (m, 2H), 2.47-2.37 (m, 2H), 2.10 (dt, J=4.5, 13.1 Hz, 2H), 1.72-1.65 (m, J=11.5 Hz, 2H); ESI MS (m/z) 366 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:27]([OH:29])[CH3:28])[C:14]([NH:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[O:26][C:14]([C@H:13]([NH:12][C:6]3[C:7]4[CH:11]=[CH:10][S:9][C:8]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C@H:27]([OH:29])[CH3:28])=[N:16][N:17]=2)=[CH:24][CH:23]=1.[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[C:8]1=2
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(F)cc2)o1
Product: N#Cc1cccc2ccsc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 215.7 %

Procedure:
To a solution of N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.41 g, 0.99 mmol) in THF (80 mL) was added PS-BEMP (1.36 g, 2.99 mmol, ˜2.2 mmol/g) and p-TsCl (191 mg, 1.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-(1R,2R)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (170 mg, 43%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.84 (d, J=5.6 Hz, 1H), 7.71 (d, J=5.6 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.13 (dd, J=6.4, 8.8 Hz, 1H), 4.66 (d, J=6.1 Hz, 1H), 4.57 (m, 1H), 1.48 (d, J=6.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:26]=[CH:25][C:24]2[N:23]=[CH:22][C:21]3[N:27]([CH3:42])[C:28](=[O:41])[N:29]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([CH3:40])([CH3:39])[C:37]#[N:38])=[CH:32][CH:31]=4)[C:20]=3[C:19]=2[CH:18]=1>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:36]([C:33]1[CH:32]=[CH:31][C:30]([N:29]2[C:20]3[C:19]4[CH:18]=[C:17]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH:26]=[CH:25][C:24]=4[N:23]=[CH:22][C:21]=3[N:27]([CH3:42])[C:28]2=[O:41])=[CH:35][CH:34]=1)([CH3:40])[C:37]#[N:38]
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4ccncc4)ccc3ncc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
37 mg (0.3 mmol) of 4-pyridineboronic acid (Aldrich, Buchs, Switzerland), 8 mg of bis(triphenylphosphine)palladium (II) dichloride (Fluka, Buchs, Switzerland) and 0.5 ml of a 1 M solution of Na2CO3 are added to a solution of 84 mg (0.2 mmol) of 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1i) in 2 ml of DMF. The mixture is stirred for 1 h at 100° C. After this time, the mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is loaded on silica gel and purified by flash chromatography (CH2Cl2-MeOH 97:3 to 18:1) to give the title compound as an off-white solid. ES-MS: 420 (M+H)+; analytical HPLC: tret=2.40 min (Grad 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)[N:7]=1)[CH2:9]2
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Clc1nccc(N2CC3CCC(C2)O3)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nccc(N3CC4CCC(C3)O4)n2)cc1
Yield: 82 %

Procedure:
3-(2-Chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3, 564 mg, 2.5 mmol) and 4-aminophenylboronic acid, pinacol ester (602 mg, 2.75 mmol) are dissolved in toluene (25 mL) and EtOH (15 mL). A 2M solution of Na2CO3 is added (5 mL) and the mixture is degassed by leading a stream of nitrogen through the solution. Tetrakis(triphenylphosphine) palladium is added (144 mg, 5 mol %) and the mixture is heated under reflux for 48 hours. The mixture is diluted with EtOAc, washed with saturated NaHCO3, the organic phase is dried (MgSO4), filtered, and concentrated. The mixture is purified by silica gel chromatography using a gradient of ethyl acetate in hexanes (40-100%) to give 576 mg (2.04 mmol, 82%) of 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline. RT 1.51, M+H=283.1
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH3:22]>CCOCC>[C:1]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCO
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC
Reaction time: 40 h
Yield: 90 %

Procedure:
A mixture containing Catalyst A (0.05 g) and oleic acid (1.41 g, 5 mmol) and ethanol (10 ml) was refluxed with stirring for 40 h. On cooling ether (30 ml) was added and the catalyst was filtered off. The organic washings were combined and concentrated to give ethyl oleate as an oil (1.39 g, 90% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30](N(OC)C)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:31])[N:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: CCOc1ccc(-c2nc(CCC(=O)N(C)OC)cs2)cc1OCC
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(-c2nc(CCC(=O)c3nccs3)cs2)cc1OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution (2 ml) of thiazole (129 mg, 1.5 mmol) in THF was cooled to −70° C., and n-butyllithium (a 2.44M hexane solution) (0.62 ml, 1.5 mmol) was added, and the resulting mixture was stirred at −70° C. for 30 minutes. A solution (4 ml) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide (500 mg, 1.4 mmol) in THF was added to the reaction mixture, followed by stirring at −70° C. for 3 hours. After heating to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 350 mg (yield: 66%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-thiazole-2-yl-1-propanone as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=1)=[O:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:20]([O:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:19])[CH:17]=[CH:16][N:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)c1cc[nH]c(=O)c1)c1ccc(Cl)cc1Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CC(C(=O)c1ccnc(OCc2ccccc2)c1)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 59.8 %

Procedure:
This material was re-benzylated as follows: 4-[2-(2,4-Dichloro-phenyl)-propionyl]-1H-pyridin-2-one (100 mg) was dissolved in absolute benzene (6 mL) and silver carbonate (65 mg) and benzyl bromide (70 mg, 0.05 mL) were added. The mixture was stirred at 50° C. over night and was then poured into ice water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (20 g silica gel, gradient of ethyl acteate in heptane (0 to 20%)) to give 1-(2-benzyloxy-pyridin-4-yl)-2-(2,4-dichloro-phenyl)-propan-1-one (78 mg) as a colorless oil. MS (m/e)=386.0 [MH+].
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:2][CH3:1])[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1
Reactant: CN
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 25 °C
Yield: 37.2 %

Procedure:
To methylamine (2.0 M in tetrahydrofuran, 16 mL, 32 mmol) was added a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (3.0 g, 6.3 mmol) in DMF (10 mL) and the mixture stirred at ambient temperature. After 4 hours the reaction mixture was poured into water (100 mL), concentrated in vacuo to remove the tetrahydrofuran and extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine (75 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 1.1 g (38% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6/TFA) 11.4 (s, 1), 11.0 (s, 1), 8.9 (br s, 2), 7.6-8.4 (m, 7), 4.2 (m, 2), :2.6 (m, 3) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NC(CO)CO)cc1
Temperature: 60 °C
Yield: 3.3 %

Procedure:
2 g of para-fluoronitrobenzene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.55 g of 2-amino-1,3-propanediol, and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured-into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water, and then dried over P2O5. 0.1 g of 2-(4-nitrophenylamino)propane-1,3-diol (15) was obtained after purification on a column of silica.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:49](=O)[CH2:50][CH3:51]>O.ClCCCl.C(O)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][N:14]([CH2:49][CH2:50][CH3:51])[C:15]3[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=3)[CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC=O
Reactant: O=Cc1nc(-c2ccccc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2cccc(N)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1cccc(COc2ccc(CCC(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a mixture of 4-phenyl-1,3-thiazole-2-carbaldehyde (210 mg, 1.1 mmol), methyl 3-{4-[(3-aminobenzyl)oxy]phenyl}-propanoate (285 mg, 1.0 mmol), acetic acid (0.2 mL) and 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.6 g, 2.8 mmol) under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 hr. Propanal (200 mg, 3.4 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:2 in volume ratio) to give the title compound (393 mg, yield 78%) as a yellow oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]12([C:23]([C:26]3[C:31](O)=[CH:30][C:29]([OH:33])=[CH:28][C:27]=3[Cl:34])=[N:24][OH:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:13]12([C:23]3[C:26]4[C:27]([Cl:34])=[CH:28][C:29]([OH:33])=[CH:30][C:31]=4[O:25][N:24]=3)[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: ON=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1cc(Cl)c2c(C34CC5CC(CC(C5)C3)C4)noc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
Diethylazodicarboxylate (0.92 g, 1.7 eq) in THF (20 ml) was added to a mixture of 1-adamantyl (2-chloro-4,6-dihydroxyphenyl)methanone oxime (1 g, 3.1 mmoles), triphenyl phosphine (1.4 g, 1.7 eq) in THF (20 ml) at 0° C. The mixture was stirred 2 h at 0° C., poured into water, extracted with ethylacetate, dried over Na2SO4 and concentrated under vacuum to give the crude product. Flash chromatography (AcOEt/toluene 1/9) and crystallisation from EtOH yielded the expected product (230 mg, 23%). mp 215° C.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:20]>O>[C:12]1([C:10]2[O:11][C:7]3[C:8](=[C:3]([CH:2]=[O:20])[CH:4]=[CH:5][CH:6]=3)[N:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrC(Br)c1cccc2oc(-c3ccccc3)nc12
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cccc2oc(-c3ccccc3)nc12

Procedure:
5.5 g (14.9 mmol) of the compound from Example XII were stirred at 100° C. with 30 ml of concentrated sulphuric acid for 1 h, the mixture was poured into water, and the precipitate was filtered off with suction and dried.